CZ293815B6 - Phthalazinone derivatives - Google Patents

Abstract

In the present invention, there are disclosed phthalazinone derivatives of the general formula I, which are compounds exhibiting bronchodilator activity and they can be used in the form of a pharmaceutical preparation, forming also a part of the present invention, which can be used for treating airways diseases.

Description

Technical field

The invention relates to novel phthalazinone derivatives which can be used for the production of pharmaceutical compositions.

BACKGROUND OF THE INVENTION

International patent application WO 91/12251 describes phthalazinones with a bromodilating effect and an inhibiting effect on thromboxane A2 synthetase. Another patent application WO 14/12461 discloses 3-arylpyridazin-6-one derivatives as selective PDE4 inhibitors.

SUMMARY OF THE INVENTION

It has now been found that another group of phthalazinones has surprising and very advantageous pharmacology properties.

The present invention provides phthalazinone derivatives of the formula I

where

R1 is C1 -C4 alkoxy optionally fully or predominantly substituted by fluorine atoms,

R 2 is C 1 -C 8 alkoxy, C 3 -C 7 cycloalkoxy, C 3 -C 7 cycloalkylmethoxy or C 1 -C 4 alkoxy, fully or predominantly substituted by fluorine atoms,

R3 and R4 are hydrogen or together form a chemical bond,

R 5 has the meaning R 6 or represents one of the groups -C _{m H2m} R _H2n --C (O) R8, -CH (R9) ₂ or -C _p H _2p -Ar, wherein

R6 is hydrogen, alkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, cycloalkylmethyl of 3 to 7 carbon atoms in the alkyl moiety, alkenyl or alkynyl of 3 to 7 carbon atoms, phenylalkenyl of 3 to 7 carbon atoms in the alkenyl moiety, polycycloalkyl of 7 to 10 carbon atoms, naphthyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, quinazolinyl, quinoxalinyl, cinolinyl, isoquinolyl, quinolyl, indanyl, benzoxazolyl, benzothiazolyl, oxazolyl, thiazolyl, tetrahydropyranpiperidyl, tetrahydropyranpiperidyl, tetrahydropyranpiperidyl, phenyl, unsubstituted or substituted with groups R61 and / or R62, wherein

-1 CZ 293815 B6

R61 represents alkyl or alkoxy of 1 to 4 carbon atoms, nitro, halogen, carboxyl, carboxalkyl, alkoxycarbonyl, hydroxyalkyl, amino, mono- or dialkylamino, alkylcarbonylamino, aminocarbonyl, mono- or dialkylaminocarbonyl, aminosulfonyl, mono- or di- dialkylaminosulfonyl having 1 to 4 carbon atoms each, 4-methylphenylsulfonamido, tetrazol-5-yl, 2-yl-tetrazol-5-yl having 1 to 4 carbon atoms or 2-benzyltetrazol-5-yl and

R 62 is alkyl or alkoxy of 1 to 4 carbon atoms, nitro or halogen,

R 7 is hydroxy, halogen, cyano, nitro, nitroxy-Ό-2, carboxy, carboxyphenyloxy, phenoxy, (C 1 -C 4) alkoxy, (C 3 -C 7) cycloalkoxy, (C 3 -C 7) cycloalkylmethoxy) , alkylcarbonyl, alkylcarbonyloxy, alkylcarbonylamino, alkoxycarbonyl, aminocarbonyl, mono- or dialkylaminocarbonyl, amino, mono- or dialkylamino of 1 to 4 carbon atoms in the alkyl moieties or piperidyl, piperazinyl, pyrrolidinyl, or unsubstituted or unsubstituted or unsubstituted or unsubstituted or unsubstituted or unsubstituted or unsubstituted or unsubstituted; R72,

R 71 represents hydroxy, alkyl, hydroxyalkyl or alkoxycarbonyl of 1 to 4 carbon atoms in each alkyl moiety,

R 72 is C 1 -C 4 alkyl, carboxy, aminocarbonyl or C 1 -C 4 alkoxycarbonyl,

R 8 is phenyl, naphthyl, phenanthrenyl or anthracenyl unsubstituted or substituted with R 81 and / or R 82;

R81 represents hydroxy, halogen, cyano, alkyl or alkoxy of 1 to 4 carbon atoms, carboxy, aminocarbonyl, mono- or dialkylamino carbonyl, alkylcarbonyloxy, alkoxycarbonyl, amino, mono- or dialkylamino, alkylcarbonylamino or C1-4alkoxy; carbon in the alkyl or alkoxy moiety, wherein the C 1 -C 4 alkoxy group is optionally fully or predominantly substituted by a fluorine atom and

R 82 represents a hydroxy group, a halogen atom, an alkyl or alkoxy group having from 1 to 4 carbon atoms or an alkoxy group having from 1 to 4 carbon atoms, totally or predominantly substituted by fluorine atoms,

R 9 is -C _q H _2q -phenyl,

Ar is unsubstituted phenyl, naphthyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolyl, quinolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, N-benzosuccinimidyl, imidazolyl, thrazolyl, thrazolyl, thrazolyl, thrazolyl, thrazolyl, thrazolyl, thrazolyl, thiazolyl, 2-alkylthiazol-4-yl of 1 to 4 carbon atoms in the alkyl moiety or phenyl substituted with R 10 and / or R 11,

R 10 represents hydroxy, halogen, nitro, C 1 -C 4 alkyl, trifluoromethyl, C 1 -C 4 alkoxy, carboxy, carboxyalkyl, alkylcarbonyloxy, alkoxycarbonyl, amino, mono- or dialkylamino, alkylcarbonylamino or amino-carbocarbonyl; C 1 -C 4 alkyl moieties; and

-2GB 293815 B6

R1 is hydroxy, halogen, nitro, alkyl or alkoxy of 1 to 4 carbon atoms, m is an integer of 1 to 8, n is an integer of 1 to 4, p is an integer of 1 to 6, q is an integer of 0 to 2 as well as salts of these compounds.

In one embodiment (embodiment a) of the invention, the present invention provides a phthalazinone derivative of the Formula I wherein:

R1 is C1 -C4 alkoxy optionally fully or predominantly substituted by fluorine atoms,

R 2 is C 1 -C 8 alkoxy, C 3 -C 7 cycloalkoxy, C 3 -C 7 cycloalkylmethoxy or C 1 -C 4 alkoxy, fully or predominantly substituted by fluorine atoms,

R3 and R4 are hydrogen or together form a chemical bond,

R 5 has the meaning R 6 or represents one of the groups -C _m H _{2 m} R7, -C _n H _2n -C (O) R8, -CH (R9) ₂ or -CpH _2p -Ar wherein

R6 is hydrogen, alkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, cycloalkylmethyl of 3 to 7 carbon atoms in the alkyl moiety, alkenyl or alkynyl of 3 to 7 carbon atoms, phenylalkenyl of 3 to 4 carbon atoms in the alkenyl moiety, bomyl, norbornyl adamantyl or phenyl, unsubstituted or substituted with groups R61 and / or R62, wherein

R61 represents an alkyl or alkoxy group having from 1 to 4 carbon atoms, a nitro group or a halogen atom,

R 62 is C 1 -C 4 alkyl, nitro or halogen;

R 7 represents hydroxy, halogen, cyano, nitro, carboxyl, phenoxy, C 1 -C 4 alkoxy, C 3 -C 7 cycloalkoxy, C 3 -C 7 cycloalkylmethoxy, alkylcarbonyl, alkylcarbonyl, alkylcarbonyl, alkylcarbonyl, alkylcarbonyl, alkylcarbonyl, alkylcarbonyl, alkylcarbonyl, alkylcarbonyl, alkylcarbonyl, alkylcarbonyl , aminocarbonyl, mono- or dialkylaminocarbonyl, amino, mono- or dialkylamino of 1 to 4 carbon atoms in the alkyl moieties or piperidyl, piperazinyl, pyrrolidinyl, or morpholinyl, unsubstituted or substituted by R71 and / or R72,

R71 is C1 -C4 alkyl,

R 72 is C 1 -C 4 alkyl, carboxy, aminocarbonyl or C 1 -C 4 alkoxycarbonyl,

R 8 represents phenyl, naphthyl, phenathrenyl or anthracenyl unsubstituted or substituted by R 81 and / or R 82;

- J CZ 293815 B6

R81 represents hydroxy, halogen, cyano, alkyl or alkoxy of 1 to 4 carbon atoms, carboxy, aminocarbonyl, mono- or dialkylamino carbonyl, alkylcarbonyloxy, alkoxycarbonyl, amino, mono- or dialkylamino, alkylcarbonylamino or C1-4alkoxy; carbon in the alkyl or alkoxy moiety, wherein the C 1 -C 4 alkoxy group is optionally fully or predominantly substituted by a fluorine atom and

R 82 represents a hydroxy group, a halogen atom, an alkyl or alkoxy group having from 1 to 4 carbon atoms or an alkoxy group having from 1 to 4 carbon atoms, totally or predominantly substituted by fluorine atoms,

R9 is -C _q H 2 _q -phenyl,

Ar is unsubstituted phenyl, naphthyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolyl, quinolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, thiazolyl, thiazolyl, thiazolyl, thiazolyl, thiazolyl, thiazolyl, thiazolyl, -yl of 1 to 4 carbon atoms in the alkyl moiety or phenyl substituted with R 10 and / or R 11,

R 10 represents hydroxy, halogen, nitro, C 1 -C 4 alkyl, trifluoromethyl, C 1 -C 4 alkoxy, carboxy, carboxyalkyl, alkylcarbonyloxy, alkoxycarbonyl, amino, mono- or dialkylamino, alkylcarbonylamino or aminocarbonylamino or aminocarbonyl; C 1 -C 4 alkyl moieties; and

R11 is hydroxy, halogen, nitro, alkyl or alkoxy of 1 to 4 carbon atoms, m is an integer from 1 to 8, n is an integer from 1 to 4, p is an integer from 1 to 6, q is an integer from 0 to 4 2, as well as the salts of these compounds.

C 1 -C 8 alkyl is a straight or branched chain alkyl radical of 1 to 8 carbon atoms. Examples include octyl, heptyl, isoheptyl, (5-methylhexyl), hexyl, isohexyl (4-methylpentyl), neohexyl (3,3-dimethylbutyl), neopentyl (2,2-dimethylpropyl), pentyl, isopentyl (3- methylbutyl), 1-ethylpropyl, butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and methyl.

C 1 -C 4 alkyl is a straight or branched chain alkyl radical having 1 to 4 carbon atoms. Examples are butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and methyl.

C 1 -C 4 alkoxy is a radical which, in addition to the oxygen atom, contains straight or branched chain alkyl of 1 to 4 carbon atoms. Such residues are, for example, butoxy, isobutoxy, sec-butoxy, tert-butoxy-propoxy, isopropoxy, ethoxy and methoxy.

C1-C4alkoxy, fully or predominantly substituted by fluorine atoms, is, for example, 2,2,3,3,3-pentafluoropropoxy, perfluoroethoxy, 1,2,2-trifluoroethoxy

And especially 1,1,2,2-tetrafluoroethoxy, 2,2,2-trifluoroethoxy, trifluoromethoxy and difluoromethoxy.

C1-C8alkoxy is a radical which, in addition to the oxygen atom, contains straight-chain or branched alkyl of 1 to 8 carbon atoms. Mention may be made of octyloxy, heptyloxy, isoheptyloxy (5-methylhexyloxy), hexyloxy, isohexyl- (4-methylpenthyloxy), neohexyloxy- (3,3-dimethylbutoxy-), pentyloxy-, isopentyloxy- (3-methylbutoxy-) -, 3-methylbutoxy- 2-dimethylpropoxy-), butoxy-, isobutoxy-, sec-butoxy-, tert-butoxy-, propoxy-, isopropoxy-, ethoxy- and methoxy.

C 3 -C 7 cycloalkoxy may be cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy or cycloheptyloxy, preferred groups are cyclopropyloxy, cyclobutyloxy and cyclopentyloxy.

The C 3 -C 7 cycloalkylmethoxy group may be cyclopropylmethoxy-, cyclobutylmethoxy-, cyclopentylmethoxy-, cyclohexylmethoxy- or cycloheptylmethoxy, with preferred groups being cyclopropylmethoxy-, cyclobutylmethoxy- and cyclopentylmethoxy.

C 3 -C 7 cycloalkyl may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

C 3 -C 7 cycloalkylmethyl in the cycloalkyl moiety is methyl substituted with one of the above C 3 -C 7 cycloalkyl radicals. Thus, for example, cyclopropylmethyl, cyclopentylmethyl or cyclohexylmethyl.

C 3 -C 7 alkenyl is a straight or branched chain alkenyl radical having 3 to 7 carbon atoms. Examples of preferred residues are 2-butenyl, 3-butenyl, 1-propenyl and 2-propenyl (allyl).

(C 3 -C 7) alkynyl is a straight or branched chain alkynyl radical of 3 to 7 carbon atoms. Examples of preferred radicals include 2-pentynyl, 2-butynyl, 3-butynyl and 2-propynyl (propargyl).

Polycycloalkyl of 7 to 10 carbon atoms can be bicycloalkyl or tricycloalkyl of 7 to 10 carbon atoms, for example bomyl, norbomyl or adamantyl.

The phenylalkenyl radical having from 3 to 4 carbon atoms of the valkenyl moiety is, for example, phenylpropen-3-yl.

A halogen atom is understood to mean a bromine, chlorine or fluorine atom.

C 1 -C 4 alkylcarbonyl is a carbonyl to which one of the above alkyl radicals is bonded. For example, acetyl.

Alkylcarbonyloxy contains, in addition to an oxygen atom, one of the above-mentioned alkylcarbonyl radicals. An example is acetyloxy.

Alkylcarbonylamino having 1 to 4 carbon atoms in the alkyl moiety is, for example, acetamido.

C 1 -C 4 alkoxycarbonyl is a carbonyl group to which any of the above alkoxy groups is bonded. They are, for example, ethoxycarbonyl or methoxycarbonyl.

Mono- or dialkylaminocarbonyl radicals having 1 to 4 carbon atoms in each alkyl moiety are, for example, methylaminocarbonyl, dimethylaminocarbonyl, and diethylaminocarbonyl.

Mono- or dialkylamino having 1 to 4 carbon atoms in each alkyl moiety are, for example, methylamino, dimethylamino and diethylamino.

The mono- or dialkylaminosulfonyl of 1 to 4 carbon atoms in each alkyl moiety is a sulfonyl to which one of the aforementioned mono- or dialkylamine residues is bonded. Examples are methylaminosulfonyl, dimethylaminosulfonyl and ethylaminosulfonyl.

C 1 -C 4 hydroxyalkyl is one of the above-mentioned alkyl groups, substituted with a hydroxyl group. Examples are hydroxymethyl, 2-hydroxyethyl or 3-hydroxypropyl.

The carboxyalkyl radical having 1 to 4 carbon atoms in the alkyl moiety may be, for example, carboxymethyl or carboxyethyl.

-C _m H _{2 m} -, -C _n H _2n -, -CpH _2q - can be straight chain or branched. Examples of -C _m H _2m groups include octylene, heptylene, isoheptylene (2-methylhexylene), hexylene, isohexylene (2-methylpentylene), neohexylene (2,2-dimethylbutylene), butylene, isobutylene, sec-butylene, target. butylene, propylene, isopropylene, ethylene, 1-methylmethylene and methylene groups.

Examples of -CpH _2p groups include hexylene, isohexylene (2-methylpentylene), neohexylene (2,2-dimethylbutylene), butylene, isobutylene, sec-butylene, t-butylene, isopropylene, pentylene, ethylene, 1-methylmethylene and methylene group.

Examples of -C _n H 2 _n - groups include butylene, isobutylene, sec-butylene, tert-butylene, propylene, isopropylene, ethylene, 1-methylmethylene and methylene. Examples of -C _q H _2q groups include ethylene, 1-methylmethylene and methylene. When q = 0, this group represents a covalent chemical bond.

The azaheterocyclic groups that are a component of the Ar substituent group, as defined by -C _p H _2p -Ar, and contain an -NH- amino group, such as pyrrole, imidazole, benzimidazole, benzotriazole or benzosuccinimide groups are preferably bonded to the -C _p H _2p - via atom nitrogen of the imino group.

Suitable salts of the compounds of formula I are, depending on the substitution, all acid addition salts or all salts with bases. Particular mention should be made of the pharmacologically acceptable salts with inorganic and organic acids and bases commonly used in pharmacy. Suitable salts are water-soluble and water-insoluble acid addition salts such as hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, acetic, citric, D-gluconic, benzoic, 2- (4-hydroxybenzoyl) benzoic, butyric, sulfosalicylic. , maleic, lauric, malic, fumaric, amber, oxalic, tartaric, embonous, stearic, toluenesulfonic, methanesulfonic or 3-hydroxy-2-naphthoic acids, such acids are used to prepare the salt in equimolar or different proportions depending on whether the acid is mono- or polyhydric.

Salts with bases are also suitable. Examples of such salts include lithium, sodium, potassium, calcium, aluminum, magnesium, ammonium, titanium, meglumine, or guanidine salts. In this case too, the base can be used in equimolar or different proportions in the manufacture of the salts.

Salts which are not pharmacologically acceptable and can be obtained, for example, as the first product in the preparation of the compounds of the invention on an industrial scale, can be converted into pharmacologically acceptable salts by known methods.

-6GB 293815 B6

The compounds of the invention and their salts may contain different amounts of solvents when isolated in crystalline form. Accordingly, the invention includes within its scope solvates and especially hydrates of the compounds of formula I and all solvates and especially hydrates of the salts of compounds of formula I.

Of the compounds of formula I, those in which:

R1 is C1 -C4 alkoxy or C1 -C2 alkoxy, wholly or predominantly substituted by fluorine,

R 2 is C 1 -C 4 alkoxy, C 3 -C 7 cycloalkoxy, C 3 -C 7 cycloalkylmethoxy or C 1 -C 2 alkoxy, wholly or predominantly substituted by fluorine,

R3 and R4 represent hydrogen atoms or together form another chemical bond,

R 5 is a group R 6 or one of -C _m H _{2 n -R} 7, -C _n H 2 _n -C (O) R 8, -CH (R 9) ₂ or -C _p H _{2 p} -Ar, wherein

R6 is hydrogen, alkyl of 1 to 8 carbon atoms, cycloacyl of 3 to 8 carbon atoms, cycloalkylmethyl of 3 to 7 carbon atoms in the cycloalkyl moiety, alkenyl or alkynyl of 3 to 7 carbon atoms, phenylalkenyl of 3 to 4 carbon atoms in the alkenyl moiety, bomyl, norbomyl, adamantyl, naphthyl, pyridyl, quinoxalinyl, indanyl, benzothiazolyl, N-methylpiperidyl, tetrahydropyranyl, tetrahydrothiopyranyl or phenyl, unsubstituted or substituted with R61 and / or R62, wherein

R61 represents alkyl or alkoxy of 1 to 2 carbon atoms, nitro, halogen, carboxy, carboxyalkyl, alkoxycarbonyl, hydroxyalkyl, amino, mono- or dialkylamino, aminocarbonyl, aminosulfonyl, mono- or dialkylaminosulfonyl, 4-methylphenylsulfonamido, tetrazol, 2-alkyl-tetrazol-5-yl or 2-benzyltetrazol-5-yl with alkylene moieties of 1 to 4 carbon atoms,

R 62 is alkyl or alkoxy of 1 to 2 carbon atoms, nitro or halogen,

R 7 is hydroxy, halogen, carboxy, nitroxy-O-NO ₂ , phenoxy, carboxyphenyloxy, alkoxy, alkylcarbonyl, alkylcarbonyloxy, alkylcarbonylamino, alkoxycarbonyl, aminocarbonyl, mono- or dialkylamino-amino, di- or dialkylamino; in alkyl moieties, or piperidyl, piperazinyl or morpholinyl, optionally substituted with R71 and / or R72, wherein

R 71 represents hydroxy, alkyl, hydroxyalkyl or alkoxycarbonyl, wherein the alkyl groups contain 1 to 4 carbon atoms and

R 72 is alkyl, carboxy, aminocarbonyl or alkoxycarbonyl wherein the alkyl groups contain 1 to 4 carbon atoms,

R 8 is phenyl or naphthyl, optionally substituted with R 81 and / or R 82, wherein

R81 is hydroxy, halogen, alkyl, alkoxy, alkylcarbonyloxy, alkylcarbonylamino, C1 -C4 alkyl or C1 -C2 alkoxy, fully or predominantly substituted by fluorine; and

-7EN 293815 B6

R 82 represents a halogen atom, an alkyl or alkoxy group having from 1 to 4 carbon atoms,

R 9 is -C _q H _2q -phenyl,

Ar is unsubstituted phenyl, naphthyl, pyridyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, N-benzosuccinimidyl, imidazolyl, oxazolyl, thiazolyl, 2-alkylthiazol-4-yl with C 1 -C 2 alkyl or phenyl substituted with R 10 and / or R11, wherein

R1 Notified hydroxy, halogen, alkyl, trifluoromethyl, alkoxy, carboxyl, carboxyalkyl, alkylcarbonyloxy or alkoxycarbonyl, wherein the alkyl groups or moieties contain 1 to 4 carbon atoms,

R11 is hydroxy, halogen, alkyl or alkoxy of 1 to 4 carbon atoms, m is an integer from 1 to 8, n is an integer from 1 to 4, p is an integer from 1 to 6, q is an integer from 0 to 1, as well as salts thereof.

Emphasis is also given to those compounds of formula I in which:

R1 is C1 -C4 alkoxy or C1 -C2 alkoxy, wholly or predominantly substituted by fluorine,

R2 is C1 -C4 alkoxy, C3 -C7 cycloalkoxy or C1 -C2 alkoxy, wholly or predominantly substituted by fluorine,

R3 to R4 represent hydrogen atoms or together form another chemical bond,

R 5 represents a group of R 6 or one of -C _m H _2m -R 7, -C _n H 2 _n -C (O) R 8, -CH (R 9) ₂ or -CpH _2p -Ar, wherein

R6 is hydrogen, alkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, cycloalkylmethyl of 3 to 7 carbon atoms in the cycloalkyl moiety, alkenyl or alkynyl of 3 to 7 carbon atoms, phenylalkenyl of 3 to 4 carbon atoms in the alkenyl moiety or phenyl, unsubstituted or substituted with R 61 or R 62, wherein

R61 represents an alkyl or alkoxy group having from 1 to 2 carbon atoms or a halogen atom,

R 62 is C 1 -C 2 alkyl, nitro or halogen;

R 7 represents hydroxy, carboxyl, phenoxy, alkoxy, alkylcarbonyl, alkylcarboxy, alkylcarbonylamino, alkoxycarbonyl, aminocarbonyl, mono- or dialkylaminocarbonyl, amino, mono- or dialkylamino of 1 to 4 carbon atoms in the alkyl moieties or piperidinyl or piperidinyl or piperidinyl or piperidinyl, substituted with R 71 and / or R 72, wherein

-8EN 293815 B6

R 71 represents hydroxy, alkyl, hydroxyalkyl or alkoxycarbonyl, in each case having 1 to 4 carbon atoms in the alkyl moieties; and

R 72 represents alkyl, carbonyl, aminocarbonyl or alkoxycarbonyl of 1 to 4 carbon atoms in each alkyl moiety,

R 8 is phenyl or naphthyl, unsubstituted or substituted with R 81 and / or 82, wherein

R 81 is hydroxy, halogen, alkyl, alkoxy, alkylcarbonyloxy, C 1 -C 4 alkylcarbonylamino, or C 1 -C 2 alkoxy, wholly or predominantly substituted by fluorine; and

R 82 represents a halogen atom, an alkyl or an alkoxy group having from 1 to 4 carbon atoms each,

R 9 is -C _q H _2q -phenyl,

Ar is unsubstituted phenyl, naphthyl, pyridyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, imidazolyl, oxazolyl, thiazolyl, 2-alkylthiazol-4-yl of 1 to 2 carbon atoms in the alkyl moiety or phenyl substituted with R 10 and / or R11, where

R1 Notified hydroxy, halogen, allyl, trifluoromethyl, alkoxy, carboxyl, carboxyalkyl, alkylcarbonyloxy or C1-4 alkoxycarbonyl in the alkyl moieties and

R11 is hydroxy, halogen, alkyl or alkoxy of 1 to 4 carbon atoms and m is an integer of 1 to 8 n is an integer of 1 to 4 p is an integer of 1 to 4 q is an integer of 0 or 1 and salts thereof compounds.

The compounds of formula (I) which should be particularly emphasized are those in which

R1 is methoxy, ethoxy or difluoromethoxy,

R2 is C1 -C4 alkoxy, difluoromethoxy, cycloalkoxy or C3 -C5 cycloalkylmethoxy, in the cycloalkyl moiety,

R 3 and R 4 represent hydrogen atoms or together form another chemical bond.

R5 represents a group selected from R 6 or a group selected from -C _H2m -R7, -C _n H _2n -C (O) R8, -CH (R9) ₂ or -C _p H _2p -Ar, wherein

R6 is hydrogen, alkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkylmethyl of 3 to 7 carbon atoms in the cycloalkyl moiety, alkenyl or alkynyl of 3 to 4 carbon atoms, phenylalkenyl of 3 to 4 carbon atoms in the alkenyl moiety, phenylalkenyl of 3 to 4 carbon atoms in the alkenyl moiety, adamantyl, pyridyl, quinoxalinyl, indanyl, benzothiazolyl,

-9EN 293815 B6

N-methylpiperidyl, tetrahydropyranyl, tetrahydrothiopyranyl or phenyl, unsubstituted or substituted by R61 and / or R62,

R61 is alkyl or alkoxy of 1 to 2 carbon atoms, nitro, halogen, carboxy, carboxyalkyl of 1 to 2 carbon atoms in the alkyl moiety, alkoxycarbonyl of 1 to 4 carbon atoms in the alkyl moiety, hydroxyalkyl of 1 to 2 carbon atoms, amino , aminosulfonyl, 4-methylphenylsulfonamido, 2-alkylthiazol-5-yl of 1 to 2 carbon atoms in the alkyl moiety or 2-benzyltetrazol-5-yl,

R 62 is alkyl of 1 to 2 carbon atoms or halogen,

R 7 represents hydroxy, halogen, carboxyl, nitro, phenoxy, carboxyphenyloxy, alkoxycarbonyl, aminocarbonyl, mono- or dialkylaminocarbonyl, amino, mono- or dialkylamino or piperidyl, piperazinyl or morpholinyl, unsubstituted or substituted with R 71, R 71

R 71 represents hydroxy, alkyl, hydroxyalkyl or alkoxycarbonyl of 1 to 4 carbon atoms in each alkyl moiety; and

R 72 represents alkyl, carboxyl, aminocarbonyl or alkoxycarbonyl each having 1 to 4 carbon atoms in the alkyl moieties,

R 8 is phenyl or naphthyl unsubstituted or substituted with R 81;

R 81 represents a halogen atom or an alkoxy group having 1 to 4 carbon atoms,

R 9 is -C _q H _2q -phenyl,

Ar is unsubstituted phenyl, naphthyl, pyridyl, benzimidazolyl, benzotriazolyl, N-benzosuccinimidyl, imidazolyl, thiazolyl, 2-alkylthiazol-4-yl of 1 to 2 carbon atoms in the alkyl moiety or phenyl substituted with R10 and / or R11

R10 represents hydroxyl, halogen, alkyl, trifluoromethyl, alkoxy, carboxyl, carboxyalkyl or alkoxycarbonyl of from 1 to 4 carbon atoms in the alkyl moieties,

R11 represents a halogen atom, an alkyl or alkoxy group having from 1 to 2 carbon atoms, m represents an integer from 1 to 8, n represents an integer from 1 to 6, p represents an integer from 1 or 2, q represents an integer from 0 or 1; salts of these compounds.

The compounds of formula (I) which are also of particular interest are those in which the compounds of formula (I) are particularly preferred

R1 is methoxy, ethoxy or difluoromethoxy,

R2 is C1 -C4 alkoxy, difluoromethoxy or C3 -C5 cycloalkoxy,

R3 and R4 represent hydrogen atoms or together form another chemical bond,

-10GB 293815 B6

R 5 is a group R 6 or one of -C _m H 2 _m -R 7, -C _n -H _{n n} -C (O) R 8, -CH (R 9) ₂ or -C _p H _2p -Ar, wherein

R6 is hydrogen, alkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, cycloalkylmethyl of 3 to 7 carbon atoms in the cycloalkyl moiety, alkenyl or alkynyl of 3 to 4 carbon atoms, phenylalkenyl of 3 to 4 carbon atoms in alkenyl moieties or phenyl, unsubstituted or substituted by R 61 and / or R 62, wherein

R 61 represents an alkyl or alkoxy group having from 1 to 2 carbon atoms or a halogen atom;

R 62 is alkyl of 1 to 2 carbon atoms or halogen,

R7 represents hydroxy, carboxyl, phenoxy, alkoxycarbonyl, aminocarbonyl, mono- or dialkylaminocarbonyl, amino, mono- or dialkylamino or piperidyl, piperazinyl, morpholinyl, unsubstituted or substituted by R71 and / or R72, wherein

R71 is hydroxy, alkyl, hydroxyalkyl or alkoxycarbonyl having an alkyl moiety of from 1 to 4 carbon atoms each,

R 72 represents alkyl, carboxyl, aminocarbonyl, or C 1 -C 4 alkoxycarbonyl,

R 8 is phenyl or naphthyl, unsubstituted or substituted with R 81,

R 81 represents a halogen atom or an alkoxy group having 1 to 4 carbon atoms,

R 9 represents-C _q H _2q -phenyl,

Ar represents unsubstituted phenyl, naphthyl, pyridyl, benzotriazolyl, triazolyl, 2-alkylthiazol-4-yl of 1 to 2 carbon atoms in the alkyl moiety or phenyl substituted with R10 and / or R11, wherein

R10 represents hydroxy, halogen, alkyl, trifluoromethyl, alkoxy, carboxyl, carboxyalkyl or alkoxycarbonyl of 1 to 2 carbon atoms in each alkyl moiety,

R11 represents a halogen atom, an alkyl or alkoxy group having from 1 to 2 carbon atoms, m represents an integer from 1 to 6, n represents an integer from 1 or 2, p represents an integer from 1 or 2, q represents an integer from 0 or 1; of these substances.

Preferred compounds of formula I are those wherein:

R 1 is methoxy or ethoxy,

R2 is methoxy, ethoxy, difluoromethoxy, cyclopropylmethoxy or cyclopentyloxy,

-11 CZ 293815 B6

R3 and R4 represent hydrogen atoms or together form another chemical bond,

R 5 is a group R 6 or one of -C _m H _2m -R 7, -C _n H 2 _n -C (O) R 8, -CH (R 9) ₂ or -C _p H _2p -Ar,

R 6 is hydrogen, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 7 cycloalkylmethyl in the cycloalkyl moiety, allyl, 2-propynyl, phenyl-transprop-1-en-3-yl, adamantyl, pyridyl, quinoxalinyl, indanyl, benzothiazolyl, N-methylpiperidyl, tetrahydropyranyl, tetrahydrothiopyranyl or phenyl, unsubstituted or substituted with R61,

R61 is C1-C4alkyl, nitro, halogen, carboxyl, carboxymethyl, hydroxyalkyl of 1 to 2 carbon atoms, amino, aminosulfonyl, 4-methylphenylsulfonylamido, 2-ethyltetrazol-5-yl or 2-benzyltetrazole-5 -yl,

R 7 is hydroxy, halogen, carboxyl, nitroxy, phenoxy, carboxyphenyloxy, C 1 -C 4 alkoxycarbonyl, amino, methylamino, dimethylamino, dimethylaminocarbonyl, 1-piperidyl or N-methyl-4-piperidyl

R 8 is phenyl, 2-methoxyphenyl, 4-chlorophenyl or 2-naphthyl,

R 9 is -C _q H _2q -phenyl,

Ar is unsubstituted phenyl, pyridyl, benzimidazolyl, benzotriazolyl, N-benzosuccinimidyl, imidazolyl, 2-methylthiazol-4-yl or phenyl substituted with R 10 and / or R 11,

R1Recognized hydroxy, halogen, methoxy, trifluoromethyl, carboxyl, carboxymethyl or methoxycarbonyl,

R11 is methoxy, m is an integer from 1 to 8, n = 1, p is an integer from 1 to 6, q = 0, and salts thereof.

Further preferred compounds of formula (I) of embodiment (a) are those in which:

R1 is methoxy or ethoxy,

R2 is methoxy, ethoxy or cyclopentyloxy,

R3 and R4 represent hydrogen atoms or together form another chemical bond,

R 5 has the meaning R 6 or represents one of the groups -C _{m H2m} -R7, -C _n H _2n -C (O) R8, -CH (R9) ₂ or -C _p H _2p -Ar, wherein

-12GB 293815 B6

R6 is hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, cycloalkylmethyl of 3 to 7 carbon atoms in the alkyl moiety, allyl, 2-propynyl, phenyl or phenyltrans-prop-1-en-3- yl,

R 7 is hydroxy, carboxyl, phenoxy, C 1 -C 4 alkoxycarbonyl, dimethylamino, dimethylaminocarbonyl, 1-piperidyl or N-methyl-4-piperidyl,

R 8 is phenyl, 2-methoxyphenyl, 4-chlorophenyl or 2-naphthyl,

R 9 is-C _q H _2q -phenyl,

Ar is unsubstituted phenyl, pyridyl, benzotriazolyl, 2-methyltriazol-4-yl or phenyl substituted with R 10 and / or R 11,

R1Recognized hydroxy, halogen, methoxy, trifluoromethyl, carboxyl, carboxymethyl or methoxycarbonyl and

R11 is methoxy, m is an integer from 1 to 6, n = 1, p is an integer of 1 or 2, q = 0, and salts of these compounds.

Particularly preferred are those compounds of formula I in which:

R1 is methoxy,

R2 is methoxy, ethoxy, difluoromethoxy, cyclopropylmethoxy or cyclopentyloxy,

R3 and R4 represent hydrogen atoms or together form another chemical bond,

R 5 is R 6 or -C _n H 2 _n -C (O) R 8 or -C _p H _{2 p} Ar,

R6 represents alkyl of 3 to 8 carbon atoms, cycloalkyl of 5 to 8 carbon atoms, cycloalkylmethyl of 3 to 7 carbon atoms in the cycloalkyl moiety, adamantyl, quinoxalinyl, indanyl, benzothiazolyl, tetrahydropyranyl, tetrahydrothiopyranyl or phenyl, unsubstituted or substituted by R61,

R 61 represents alkyl of 1 to 4 carbon atoms, nitro, halogen, carboxy, carboxymethyl, hydroxyalkyl of 1 to 2 carbon atoms, aminosulfonyl, 4-methylphenylsulfonamido, 2-ethyltetrazol-5-yl or 2-benzyltetrazol-5-yl,

R 8 is phenyl or 2-naphthyl,

Ar is unsubstituted phenyl, benzimidazolyl, N-benzosuccinimidyl, imidazolyl or phenyl substituted with R10,

-13GB 293815 B6

R10 is hydroxy, halogen, methoxy, trifluoromethyl or carboxyl, n = 1, p is an integer from 1 to 6, and salts thereof.

Particularly preferred compounds of formula (I) in embodiment (a) are also those in which:

R 1 is methoxy or ethoxy,

R2 is methoxy, ethoxy or cyclopentyloxy,

R3 and R4 represent hydrogen atoms or together form another chemical bond,

R 5 represents a group R 6 or one of the groups -C _m H _{2 m} -R 7, -C _n H 2 _n -C (O) R 8, -CH (R 9) ₂ or CpH ₂ p Ar, wherein:

R 6 represents alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, cycloalkylmethyl of 3 to 7 carbon atoms in the cycloalkyl moiety, allyl, 2-propynyl, phenyl or phenyl-transprop-1-en-3-yl,

R7 is hydroxy, carboxyl or phenoxy,

R 8 is phenyl, 2-methoxyphenyl, 4-chlorophenyl or 2-naphthyl,

R 9 is-C _q H 2 -phenyl,

Ar is unsubstituted phenyl, pyridyl, benzotriazolyl, 2-methylthiazolyl-4-yl or phenyl substituted with R10 and / or R11,

R1 Notified hydroxy, halogen, methoxy, trifluoromethyl carboxyl, carboxymethyl or methoxycarbonyl,

R11 is methoxy, m is an integer from 1 to 6, n = 1, p is an integer of 1 or 2, q = 0, and salts of these compounds.

The compounds of formula I are chiral compounds with chiral centers in the 4a and 8a positions

-14GB 293815 B6

The invention therefore encompasses all existing pure diastereomers and pure enantiomers as well as all mixtures thereof in any ratio including racemates. Preferred are those in which the hydrogen atom in the 4a and 8a positions has a cis configuration, particularly preferred are those in which the absolute S configuration at the 4a position in the R position is 8a according to the rules of Cahn, Ingold and Prelog. The racemates can be resolved into the corresponding enantiomers by known methods. Preferably, the racemic mixtures are separated using an optically active resolving agent at the cyclohexanecarboxylic acid stage starting from compounds A, B, D and G or the 1,2,3,6-tetrahydrobenzoic acid starting stage from compounds C, E and F of the reagents suitable for use in this resolution include, for example, optically active amines such as (+) - and (-) - forms of alpha-phenylethylamine and ephedrine, or optically active alkaloids cinchonine, cinchonidine and brucine.

Another object of the present invention is to provide a process for the preparation of the compounds of the formula I and their salts which comprises:

a) reacting the keto acids of formula II

or a reactive derivative thereof in which R1, R2, R3 and R4 are as defined above, in the first step with hydrazine hydrate to give compounds of formula I

wherein R1, R2, R3 and R4 are as defined above and R5 is hydrogen.

If desired, they can be reacted with alkylating agents of formula R5-X, wherein R5 is as defined above except for hydrogen and X is a cleavable moiety.

A further derivative of the general formula I is obtained in which R1, R2, R3, R4 and R5 are as defined above except for the hydrogen atom for R5.

b) keto acids of formula II or their reactive derivatives in which R2, R3 and R4 are as hereinbefore defined may also be reacted with a hydrazine derivative of formula _R5-NH-NH2, wherein R5 is defined as above except for the atom hydrogen to give compounds of formula I wherein R1, R2, R3, R4 and R5 are as defined above except for the hydrogen atom for R1.

The reaction of the keto acids of the formula II or their reactive derivatives with the hydrazine hydrate according to process a) or with a suitable hydrazine derivative according to process b) is preferably carried out using 1 to 5 equivalents of hydrazine hydrate or hydrazine derivative. Preferably, however, the process is carried out in a suitable solvent. The inert solvents for use herein are preferably alcohols such as methanol, ethanol, isopropanol, n-butanol, isoamyl alcohol, glycols and their ethers such as ethylene glycol, diethylene glycol, ethylene glycol monomethyl ether or monoethyl ether, carboxylic acids. , for example, formic, acetic or propionic acid, and also suitable mixtures of said solvents and mixtures thereof with water, for example a mixture of water and ethanol, and ethers, preferably water-soluble, such as tetrahydrofuran, dioxane or ethylene glycol dimethyl ether, and toluene or benzene. Azeotropic distillation is used to remove the reaction water.

The reaction temperature is 0 to 200, preferably 20 to 100 ° C, and the reaction time is 1 to 48 hours.

Suitable reactive ketoacid derivatives of the formula II which may be mentioned are, for example, esters, in particular methyl and ethyl esters, nitriles and acid halides, for example their chlorides and bromides. These compounds can be prepared by the corresponding keto acids of the formula II according to known methods.

Conversion of derivatives of formula I wherein R1, R2, R3 and R4 are as defined above and R5 is hydrogen by alkylating agents of formula R5-X wherein R5 is as defined above except hydrogen and X is a leaving group is can be carried out in a known manner.

In the first step, the hydrogen atom in the -NH group of compounds of formula I in which R5 is hydrogen is removed by treatment with a base such as potassium carbonate, sodium hydroxide, sodium hydride, sodium methoxide or sodium ethoxide, or butyllithium in a suitable solvent such as dimethylformamide. dimethylsulfoxide, tetrahydrofuran or diethyl ether. The alkylation is then carried out by addition of an appropriate alkylating agent of the formula R5-X.

The base is preferably used in an amount greater than an equimolar amount, preferably at 0 to 150 ° C.

Examples of suitable leaving groups in the meaning of X include halogen atoms, especially chlorine, or hydroxyl groups activated by esterification, for example p-toluenesulfonic acid.

Suitable alkylating agents of the formula R5-X are, for example, iodomethane, bromoethane, 1-bromopropane, 2-bromopropane, 1-bromohexane, 3-bromopentane, cyclopentyl bromide, bromomethylcyclohexane, chloromethylcyclopropane, cycloheptyl bromide, allyl chloride, propane-3-chloro, propanol. propanol, 6-bromohexanoic or 8-bromooctanoic acid, 2-bromomethyl-N, N-dimethylamine, ethylbromoacetate, 4-chloro-N-methylpiperidine, omega-bromoacetophenone, diphenylchloromethane, 3-phenoxy-1-bromopropane, 1,4-dibromobutane , 1,6-dibromohexane, omega-bromo-4-chloroacetophenone, omega-bromo-2-methoxyacetophenone, alpha-bromo-2'acetonaphthone, 4-chloromethylbenzoic acid, 3-bromomethylbenzoic acid or 4-chloro

293815 B6 methylphenylacetic acid, benzyl chloride, 2-methoxybenzyl chloride, 3-methoxybenzyl chloride, 4-methoxybenzyl chloride, 3,5-dimethoxybenzyl chloride, 2-trifluoromethylbenzyl chloride, 2-chlorobenzyl chloride, 2-picolyl chloride, 4-picolyl chloride, 4-picolyl chloride, 4-picolyl chloride, 2-methylthiazolyl, 1-bromomethylbenztriazole, 2-bromoethylbenzene, 3-phenyl-2 (trans) propenyl chloride, 4benzyloxybenzyl chloride and 2-benzyloxybenzyl chloride.

Examples of suitable hydrazine derivatives of the formula R 5 -NH-NH ₂ include methylhydrazine, 4-heptylhydrazine, cyclohexylhydrazine, cyclooctylhydrazine, adamantylhydrazine, 2hydroxyethylhydrazine, 4-tert-butylhydrazine, phenylhydrazine, 2-methylphenylhydrazine, 2-tert -butylphrazine, 4-tert -butylphrazine. , 3-hydrazinobenzoic acid or 4-hydrazinophenylacetic acid, 2- (4-hydrazinophenyl) ethanol, 4-sulfonamidophenylhydrazine, 4-nitrophenylhydrazine, 4- (2ethoxytetrazol-5-yl) phenylhydrazine, 2-benzyl-5- (4-hydrazinophenyl) tetrazole , benzylhydrazine, 2-bromophenylhydrazine, 4-chlorophenylhydrazine, 4-fluorophenylhydrazine, 2,4-dichlorophenylhydrazine, 4-chloro-o-tolylhydrazine, 2,5-dimethylphenylhydrazine, 2,4-dinitrifenylhydrazine, 4-methoxyphenylhydrazine, 3-nitrophenylhydrazine, p-tolyl 2-pyridylhydrazine, 2-indanylhydrazine, 2hydrazino-1,4-benzodiazine, 2-hydrazinobenzothiazole, 4-hydrazinotetrahydropyran and 4-hydrazinotetrahydrothiopyran.

The keto acids of formula II wherein R1, R2, R3 and R4 are as defined above may be prepared, for example, from compounds of formula III

wherein R1 and R2 are as defined above and Z is hydrogen by Friedel-Crafts acylation with compounds of formula IV

(iv) wherein R3 and R4 are as defined above.

Friedel-Crafts acylation is carried out in a manner known per se, for example according to M. Yamaguchi et al., J. Jed. Chem., 36: 4052-4060, 1993, in the presence of a suitable catalyst such as aluminum, zinc or ferric chloride or iodine in a suitable inert solvent such as methylene chloride or nitrobenzene or another inert solvent such as diethyl ether, preferably at a higher temperature, especially at the boiling point of the solvent used.

A compound of formula II wherein R1, R2, R3 and R4 are as defined above may also be prepared from compounds of formula III wherein R1 and R2 are as defined above and Z is halogen by reaction with compounds of formula IV, wherein: wherein R3 and R4 are as defined above.

Said reaction is carried out in a manner known per se, e.g.

-17GB 293815 B6

a) activates compounds of formula III wherein R1, R2 and Z are as defined above by lithium / halogen exchange at low temperature, preferably -60 to -100 ° C in an inert solvent such as tetrahydrofuran or diethyl ether, preferably under an inert atmosphere gas followed by reaction of the lithiated compounds with a cyclic carboxylic acid anhydride of formula (IV);

b) compounds of formula III in which R1, R2 and Z are as defined above in a suitable inert solvent such as tetrahydrofuran or diethyl ether to the corresponding Grignard compounds of formula III in which Z is magnesium chloride, bromide or iodide, followed by reaction of a compound of formula IV wherein R 3 to R 4 are as defined above.

Compounds of formula III in which R1 and R2 are as defined above and Z is hydrogen or halogen are known or can be prepared by methods described in the literature.

Compounds of formula IV in which R 3 and R 4 are as defined above are also known or can be prepared by known methods.

In addition, it is possible to convert a functional group in the compounds of formula I to another functional group by conventional reactions.

That is, compounds of formula I with certain functional groups can be converted to compounds of formula I with other groups.

For example, compounds of formula I wherein R 5 is an ester group can be converted by saponification with an acid or a base to the corresponding carboxyl group or converted by reaction with a suitable amine to the corresponding amide.

In addition, compounds of formula I wherein R5 is a reactive leaving group, such as a halogen atom, can be converted to the corresponding amines by reaction with a suitable amine.

Further, compounds of formula I wherein R2 is an acid labile ether linkage, such as a bond between a cyclopentyl moiety and oxygen, can be converted by acid cleavage of an ether bond into compounds of formula I wherein R2 is a hydroxyl group. Further alkylation of this hydroxyl group with the appropriate alkylating agents yields additional compounds of Formula I.

Suitable alkylating agents include, for example, chlorodifluoromethane or cyclopropylmethyl chloride.

Other transformations may be accomplished by analogous methods or procedures conventionally known in the art, for example, as described in the Examples section of the application.

The resulting products may be isolated and purified in a known manner, for example by distilling off the solvent in vacuo and recrystallizing the residue from a suitable solvent, or by other conventional means, for example by chromatography on a suitable carrier.

The salts of the derivatives according to the invention can be prepared by dissolving the free compound in a suitable solvent, for example a chlorinated hydrocarbon such as methylene chloride or chloroform or a low molecular weight aliphatic alcohol such as ethanol or isopropanol containing the desired acid or base, or the acid or base is added after the free derivative is dissolved in the solvent. The salt is then isolated by filtration, precipitation with solvents in which the addition salt does not dissolve, or evaporation of the solvent. The salts thus prepared can be converted by treatment with a base or an acid into the free compounds, which can then be converted into further salts.

-18GB 293815 B6

For example, salts which are not pharmacologically acceptable can be converted into pharmacologically acceptable salts.

The invention will now be illustrated by the following examples, which are not intended to limit the scope of the invention. When the preparation of one of the compounds of formula (I) is not mentioned directly, it can be prepared by processes analogous to those described above.

DETAILED DESCRIPTION OF THE INVENTION

Examples

Final products

Example 1)

Preparation of (cis) -4- (3,4-dimethoxyphenyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one

A solution prepared by dissolving 26.0 g; 2- (3,4-dimethoxybenzoyl) - [cis] -cyclohexanecarboxylic acid as starting material; and obtained under Example A); described below; and 19.0 g of hydrazine hydrate; in ethanol; was heated to reflux; for 4.0 hours.

After cooling the reaction mixture to room temperature, the resulting precipitate was filtered off; and dried; to give the title compound.

Melting point: 170.0 ° C;

Example 2)

Preparation of (trans) -4- (3,4-dimethoxyphenyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one

In an analogous manner to that described in the preceding Example 1); using 2- (3,4-dimethoxybenzoyl) - (trans) -cyclohexanecarboxylic acid as starting material; and obtained under Example B); described below; and hydrazine hydrate; ready prepared; the title compound.

Mp: 143.0-146 ° C;

Example 3)

Preparation of (cis) -4- (3,4-dimethoxyphenyl) -4a, 5,8,8a-tetrahydro-2H-phthalazin-1-one

Analogous procedure; described above in Example 1); using (cis) -2- (3,4-dimethoxybenzoyl) -1,2,3,6-tetrahydrobenzoic acid; as a starting material; and obtained under Example C); described below; and hydrazine hydrate; ready prepared; the title compound.

Mp: 173-174.0 ° C;

-19GB 293815 B6

Example 4)

Preparation of (cis) -4- (3-cyclopentyloxy-4-methoxyphenyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one

Analogous to the procedure described above in Example 1); using 2- (3-cyclopentyloxy-4-methoxybenzoyl) -cis-cyclohexanecarboxylic acid as the starting material; and obtained under Example D); described below; and hydrazine hydrate, prepared as desired; the title compound.

Melting point: 175.0-176.0 ° C;

Example 5)

Preparation of (cis) -4- (3-cyclopentyloxy-4-methoxyphenyl) -4a, 5,8,8a-tetrahydro-2H-phthalazin-1-one

Analogous to the procedure described above in Example 1); using (cis) -2 (3-cyclopentyloxy-4-methoxybenzoyl) -1,2,3,6-tetrahydrobenzoic acid as the starting material; and obtained under Example E); described below; and hydrazine hydrate; to obtain the title compound.

Melting point: 166.0-168.0 ° C;

Example 6)

Preparation of (cis) -4- (3-ethoxy-4-methoxyphenyl) -4a, 5,8,8a-tetrahydro-2H-phthalazin-1-one

Analogous to the procedure described above in Example 1); using (cis) -2- (3-ethoxy-4-methoxybenzoyl) -1,2,3,6-tetrahydrobenzoic acid as the starting material; and obtained under Example F); described below; and hydrazine hydrate, prepared as desired; the title compound.

Mp: 163.0-166.0 ° C;

Example 7)

Preparation of (cis) -4- (3,4-diethoxyphenyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one

Analogous to the procedure described above in Example 1); using 2- (3,4-diethoxybenzoyl) - [cis] -cyclohexanecarboxylic acid as starting material; and obtained under Example G); described below; and hydrazine hydrate; the title compound was obtained, which was purified by chromatography, eluting with dichloromethane; and recrystallization from ethyl acetate.

Mp: 156.0-157.0 ° C;

-20GB 293815 B6

Example 8)

Preparation of (cis) -4- (3,4-dimethoxyphenyl) -2-methyl-4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one

To a suspension prepared by mixing 5.0 mmol; (cis) -4- (3,4-dimethoxyphenyl) -4a, 5,6,7,8,8-hexahydro-2-phthalazin-1-one; obtained in Example 1); described above; and about 40.0 mL; dimethylformamide; was added under a nitrogen atmosphere; and at room temperature; 6.0 mmol; 60% suspension of sodium hydride in mineral oil; and the resulting reaction mixture was stirred for 30.0 minutes.

Upon completion of the above operation, 7.0 mmol; methyl iodide; and the resulting reaction mixture was stirred for an additional 4.0 hours. Then the solvent was evaporated from the mixture; and the resulting residue was partitioned between ethyl acetate; and water. After separation of the organic and aqueous phases, the organic layer was dried with magnesium sulfate; aaporized.

The residue was purified by chromatography, eluting with dichloromethane and then recrystallized from petroleum ether (b.p. 60.0-95.0 ° C).

The title compound was obtained.

Mp: 110.0-112.0 ° C;

Example 9)

Preparation of (cis) -4- (3,4- (limethoxyphenyl) -2-ethyl-4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one)

In an analogous manner to that described in the previous Example 8); using (cis) -4- (3,4-dimethoxyphenyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one; as starting material, and obtained under Example 1); described above; and bromoethane, the title compound was obtained, which was recrystallized from methanol.

Melting point: 105.0-106.0 ° C;

Example 10)

Preparation of (cis) -4- (3,4-dimethoxyphenyl) -2- (n-propyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one

Analogous to the procedure described above in Example 8); using (cid) -4- (3,4-dimethoxyphenyl) -4a, 5,6,7,8,8a-hexahydro-2-phthalazin-1-one; as a starting material; and obtained in Example 1); described above; and 1-bromopropane; the title compound was obtained, which was purified by chromatography using dichloromethane as eluent and recrystallized from petroleum ether (b.p. 60.0-95.0 ° C),

Mp: 95.0-96.0 ° C;

-21 GB 293815 B6

Example 11)

Preparation of (cis) -4- (3,4-dimethoxyphenyl) -2- (n-hexyl) -4a, 5,8,8a-tetrahydro-2H-phthalazin-1-one

Analogous to the procedure described above in Example 8); using (cis) -4- (3,4-dimethoxyphenyl) H-4a, 5,8,8a-tetrahydro-2H-phthalazin-1-one; as a starting material; and obtained under Example 3); described above; and 1-bromohexane; ready prepared; the title compound, which was purified by chromatography and recrystallized from petroleum ether (b.p. 6 DEG, 0 DEG-80 DEG C.); at minus 20.0 ° C.

Mp 74.0-75.0 ° C;

Example 12)

Preparation of (cis) -2-isopropyl-4- (3,4-dimethoxyphenyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one

Analogous to the procedure described above in Example 8); using (cis) -4- (3,4-dimethoxyphenyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one; as a starting material; obtained in Example 1); described above; and 2-bromopropane; the title compound was obtained, which was purified by chromatography using dichloromethane as eluent; and recrystallization from diethyl ether: petroleum ether; (bp 60.0-95.0 ° C).

Mp 79.0-81.0 ° C;

Example 13)

Preparation of (cis) -4- (3,4-dimethoxyphenyl) -2-isopropyl-4a, 5,8,8a-tetrahydro-2H-phthalazin-1-one

Analogous to the procedure described above in Example 8); was from (cis) -4- (3,4-dimethoxyphenyl) -4a, 5,8,8a-tetrahydro-2H-phthalazin-1-one as a starting material; and obtained under Example 3); described above; and 2-bromopropane; the title compound which has been crystallized; and then recrystallized from methanol.

Mp: 146.0-149.0 ° C;

Example 14)

Preparation of (cis) -4- (3,4-dimethoxyphenyl) -2- (tert-butyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one

Mixture prepared by mixing 2.0 g; 2- (3,4-dimethoxybenzoyl) - [cis] -cyclohexanecarboxylic acid; as a starting material; and obtained under Example A); described below; and 5.0 g; t-butylhydrazine; and 5.0 ml; triethylamine; in toluene; was heated for 20.0 hours; in DeanStark's apparatus.

The title compound was obtained, which was purified by chromatography using dichloromethane as eluent; and recrystallization from petroleum ether (bp 60.0-95.0 ° C); at minus 20.0 ° C.

Melting point: 99.0 to 101.0 ^Q C;

-22EN 293815 B6

Example 15)

Preparation of (cis) -2- (3-ethyl-propyl) -4- (3,4-dimethoxyphenyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one

Analogous to the procedure described above in Example 8); using (cis) -4- (3,4-dimethoxyphenyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one; as a starting material; and obtained in Example 1); described above; and 3-bromopentane; the title compound was obtained, which was purified by chromatography using dichloromethane; as eluent; followed by recrystallization from methanol.

Mp: 98.0-99.0 ° C;

Example 16)

Preparation of (cis) -2- (4-propyl-butyl) -4- (3,4-dimethoxyphenyl) -4a, 5,8,8a-tetrahydro-2H-phthalazin-1-one

Analogous to the procedure described above in Example 8); using (cis) -4- (3,4-dimethoxyphenyl) -4a, 5,8,8a-tetrahydro-2H-phthalazin-1-one; as a starting material; and obtained under Example 3); described above; and 4-heptylhydrazine; the title compound was obtained and purified by chromatography; and recrystallization from petroleum ether; (bp 60.0-80.0 ° C).

Mp 71.0-73.0 ° C;

Example 17)

Preparation of (cis) -4- (3,4-dimethoxyphenyl) -2-cyclopentyl-4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one

Analogous to the procedure described above in Example 8); using (cis) -4- (3,4-dimethoxyphenyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one; as starting material, and obtained under Example 1); described above; and cyclopentyl bromide, the title compound was obtained, which was recrystallized from methanol.

Melting point: 111.0-114.0 ° C.

Example 18)

Preparation of (cis) -4- (3,4-dimethoxyphenyl) -2-cyclopentyl-4a, 5,8,8a-tetrahydro-2H-phthalazin-1-one

Analogous to the procedure described above in Example 8); using (cis) -4- (3,4-dimethoxyphenyl) -4a, 5,8,8a-tetrahydro-2H-phthalazin-1-one; as a starting material; and obtained under Example 3); described above; and cycloheptyl bromide; the title compound was obtained, which was purified by chromatography using dichloromethane as eluent; followed by recrystallization from diethyl ether.

Mp: 131.0-133.0 ° C;

-23EN 293815 B6

Example 19)

Preparation of (cis) -4- (3-ethoxy-4-methoxyphenyl) -2-cyclopentyl-4a, 5,8,8a-tetrahydro-2H-phthalazin-1-one

A solution prepared by dissolving 0.50 g; (cis) -4- (3-ethoxy-4-methoxyphenyl) 4a, 5,8,8a-tetrahydro-2H-phthalazin-1-one obtained in Example 6) described above, followed by 0.80 g; carbonate potassium iodide and 0.30 g of ethyl iodide in 20.0 ml of N-methyl-pyrrolidinone were stirred at 70.0 ° C for 4.0 hours.

After completion of the above operation, the reaction mixture was cooled to room temperature; and then, after pouring into 200.0 ml; water, this mixture was extracted with diethyl ether. After separation of the organic and aqueous phases, the organic layer was dried with magnesium sulfate, and the solvent was evaporated.

The title compound was recrystallized from methanol.

Melting point: 124.0 - 127.0 ° C;

Example 20)

Preparation of (cis) -4- (3-difluoromethoxy-4-methoxyphenyl) -2-cyclopentyl-5,8,8a-tetrahydro-2H-phthalazin-1-one

Solution prepared by mixing 1.0 g; (cis) -4- (4-methoxy-3-hydroxyphenyl) -2-cyclopentyl-4α, 5,8,8α-tetrahydro-2H-phthalazin-1-one; obtained under Example H); described below; 0.06 g; tetraethylammonium bromide; and 0.36 g; sodium hydroxide in 0.50 mL of water; in 7.0 ml dioxane; at 80.0 ° C; was saturated with dichlorodifluoromethane for 30.0 minutes.

After completion of the above operation, the previous operation was after cooling to room temperature; The dioxane from the reaction mixture was decanted and then evaporated. The resulting residue was partitioned between water and ethyl acetate, and after separation of the organic and aqueous phases, the organic layer was dried with magnesium sulfate; and evaporated. The residue was purified by chromatography; crystallization from petroleum ether; (bp 60.0-80.0 ° C); to give the title compound.

Mp 124.0-125.0 ° C;

Example 21)

Preparation of (cis) -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-cyclopentyl-4a, 5,8,8a-tetrahydro-2H-phthalazin-1-one

Analogous to the procedure described above in Example 8); was from (cis) -4- (3-cyclopentyloxy-4-methoxyphenyl) -4a, 5,8,8a-tetrahydro-2H-phthalazin-1-one; as a starting material; and obtained under Example 5); described above; and cyclopentyl bromide; the title compound was obtained, which was recrystallized from diethyl ether.

Mp: 144.0-145.0 ° C;

-24GB 293815 B6

Example 22)

Preparation of (cis) -4- (3,4-dimethoxyphenyl) -2-cyclohexyl-4a, 5,8,8a-tetrahydro-2H-phthalazin-1-one

In an analogous manner to that described in Example 35); using (cis) -2- (3,4-dimethoxybenzoyl) -1,2,3,6-tetrahydrobenzoic acid as starting material; and obtained under Example C); described below; and cyclohexylhydrazine, the title compound is obtained, which is recrystallized from methanol.

Melting point: 147.0-148.0 ° C;

Example 23)

Preparation of (cis) -4- (3,4-dimethoxyphenyl) -2-cycloheptyl-4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one

Analogous to the procedure described above in Example 8); was from (cis) -4- (3,4-dimethoxyphenyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one; as a starting material; obtained in Example 1); described above; and cycloheptyl bromide, the title compound is obtained, which is recrystallized from methanol.

Mp 102-104 ° C;

Example 24)

Preparation of (cis) -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-cycloheptyl-4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one

Analogous to the procedure described above in Example 8); was from (cis) -4- (3-cyclopentyloxy-4-methoxyphenyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one; as a starting material; and obtained under Example 4); as described above, and cycloheptyl bromide, the title compound is obtained, which is recrystallized from petroleum ether; (bp 60.0-80.0 ° C).

Mp: 111.0-112.0 ° C;

Example 25)

Preparation of (cis) -4- (3,4-dimethoxyphenyl) -2-cycloheptyl-4a, 5,8,8a-tetrahydro-2H-phthalazin-1-one

In an analogous manner to that described in Example 105); was from (cis) -4- (3,4-dimethoxyphenyl) -4a, 5,8,8a-tetrahydro-2H-phthalazin-1-one as the starting material obtained in Example 3); described above; and cycloheptyl bromide, the title compound is obtained, which is recrystallized from methanol.

Mp: 92.0-93.0 ° C;

-25GB 293815 B6

Example 26)

Preparation of (cis) -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-cycloheptyl-4a, 5,8,8a-tetrahydro-2H-phthalazin-1-one

Analogous to the procedure described above in Example 8); was from (cis) -4- (3-cyclopentyloxy-4-methoxyphenyl) -4a, 5,8,8a-tetrahydro-2H-phthalazin-1-one; as starting material obtained in Example 5); described above; and cycloheptyl bromide, the title compound is obtained, which is recrystallized from petroleum ether; (60.0 to 80.0 ° C).

Mp 106.0 ° C;

Example 27)

Preparation of (cis) -4- (3-cyclopropylmethoxy-4-methoxyphenyl) -2-cycloheptyl-4a, 5,8,8a-tetrahydro-2H-phthalazin-1-one

Mixture prepared by mixing 1.40; (cis) -4- (3,4-dimethoxyphenyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one; obtained in Example 1); described above; and 0.40 g; cyclopropylmethyl chloride; 1.10 g; potassium iodide; and 0.60 g; potassium carbonate, was stirred in N-methylpyrrolidinone, at 60.0 ° C; for 5 days.

Upon completion of the above operation, the reaction mixture was partitioned between water and diethyl ether. After separation of the organic and aqueous phases, the organic layer was dried with magnesium sulfate; and then evaporated. The title compound was purified by chromatography using petroleum ether: ethyl acetate; (4: 1.0); as the eluent, followed by crystallization from petroleum ether (bp 60.0-80.0 ° C).

Mp: 102.0-103.0 ° C;

Example 28)

Preparation of (cis) -4- (3-difluoromethoxy-4-methoxyphenyl) -2-cycloheptyl-4a, 5,8,8a-tetrahydro-2H-phthalazin-1-one

Analogous to the procedure described above in Example 20); was from (cis) -4- (3,4-dimethoxyphenyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one; as starting material obtained in Example 1); of the title compound, which was recrystallized from dichloromethane: petroleum ether (b.p. 60.0-80.0 ° C).

Mp: 83.0 ° C;

Example 29)

Preparation of (cis) -4- (3,4-Dimethoxyphenyl) -2-cyclooctyl-4a, 5,8,8a-tetrahydro-2H-phthalazin-1-one

In an analogous manner to that described in Example 35); was from (cis) -4- (3,4-dimethoxyphenyl) -4a, 5,8,8a-tetrahydro-2H-phthalazin-1-one; as a starting material obtained in the above-described Example 3); and cyclooctylhydrazine; the title compound was obtained, which was purified by chromatography using dichloromethane as eluent and recrystallized from petroleum ether; (bp 40.0-60.0 ° C).

-26GB 293815 B6

Mp 75.0-77.0 ° C;

Example 30)

Preparation of (cis) -4- (3,4-dimethoxyphenyl) -2-adamantyl-4a, 5,8,8a-tetrahydro-2H-phthalazin-1-one

In an analogous manner to that described in Example 35); was from (cis) -4- (3,4-dimethoxyphenyl) -4a, 5,8,8a-tetrahydro-2H-phthalazin-1-one; as a starting material obtained in the above-described Example 3); and adamantylhydrazine hydrochloride; to give the title compound which was recrystallized from methanol.

Mp: 157.0-159.0 ° C;

Example 31)

Preparation of (cis) -4- (3,4-dimethoxyphenyl) -2-cyclopropylmethyl-4a, 5,8,8a-tetrahydro-2H-phthalazin-1-one

Analogous to the procedure described above in Example 8); was from (cis) -4- (3,4-dimethoxyphenyl) -4a, 5,8,8a-tetrahydro-2H-phthalazin-1-one; as a starting material obtained in the above-described Example 3); and chloromethylcyclopropane; the title compound was obtained, which was crystallized from diethyl ether; and recrystallized from methanol.

Melting point: 142.0-145.0 ° C;

Example 32)

Preparation of (cis) -2-cyclohexylmethyl-4- (3,4-dimethoxyphenyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one

Analogous to the procedure described above in Example 8); was from (cis) -4- (3,4-dimethoxyphenyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one; as a starting material; and obtained as described in Example 1) above; and bromomethylcyclohexane; the title compound was obtained, which was crystallized from petroleum ether; (bp 60.0-95.0 ° C).

Mp: 137.0-139.0 ° C;

Example 33)

Preparation of (cis) -2-allyl-4- (3,4-dimethoxyphenyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one

Analogous to the procedure described above in Example 8); was from (cis) -4- (3,4-dimethoxyphenyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one as the starting material; obtained under Example 1 above); and allyl chloride; the title compound was obtained and purified by chromatography; eluting with dichloromethane; and crystallization from petroleum ether; (bp 60.0-95.0 ° C).

Mp 99.0-101.0 ° C;

-27GB 293815 B6

Example 34)

Preparation of (cis) -4- (3,4-dimethoxyphenyl) -2-propargyl-4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one

An analogous procedure to that described in Example 8 above was that of (cis) -4- (3,4-dimethoxyphenyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one such as the starting material obtained in the above-described Example 1); and propargyl bromide, the title compound is prepared, except that instead of sodium hydride; sodium ethoxide was used; and the compound thus obtained was purified by chromatography, eluting with dichloromethane, followed by crystallization from methanol.

Mp 118.0-121.0 ° C;

Example 35)

Preparation of (cis) -4- (3,4-dimethoxyphenyl) -2- (2-hydroxy-1-ethyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one

Solution prepared by dissolving 2,0 g; 2- (3,4-dimethoxybenzoyl) - [cis] -cyclohexanecarboxylic acid; as a starting material; and obtained under Example A) described below; further 2.0 g; 2-hydroxyethylhydrazine, in a mixture prepared by mixing 100.0 mL; 1-propanol; and 5.0 ml; triethylamine; was heated at reflux for 18 hours.

After the previous operation described above, the solvent from the reaction mixture was evaporated; and the resulting residue was partitioned between aqueous sodium carbonate; and ethyl acetate. The title compound was crystallized from diethyl ether by further operations; and at a minute temperature of 20.0 ° C; was recrystallized from methanol.

Melting point: 128.0 to 129.0 ° C;

Example 36)

Preparation of (cis) -2- (3-hydroxy-1-propyl) -4- (3,4-dimethoxyphenyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one

Analogous to the procedure described above in Example 8); was from (cis) -4- (3,4-dimethoxyphenyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one; as a starting material obtained in the above-described Example 1); and 3-bromo-1-propanol; the title compound was obtained, which was recrystallized from diethyl ether: petroleum ether; (bp 60.0-95.0 ° C).

Mp: 94.0-97.0 ° C;

Example 37)

Preparation of ethyl- (cis) -4- (3,4-dimethoxyphenyl) -1-oxo-4a, 5,6,7,8,8a-hexahydro-1H-phthalazin-2-yl) -acetic acid

Analogous to the procedure described above in Example 8); was from (cis) -4- (3,4-dimethoxyphenyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one as the starting material obtained in the frame

293815 B6 or Example 1 above); and ethyl bromoacetate to give the title compound, which was minus 20.0 ° C; recrystallized from ethanol.

Melting point: 97.0 to 99.0 ° C;

Example 38)

Preparation of (cis) - [4- (3,4-Dimethoxyphenyl) -1-oxo-4a, 5,6,7,8,8a-hexahydro-1H-phthalazin-2-yl] acetic acid

Mixture prepared by stirring ethyl- (cis) -4- (3,4-dimethoxyphenyl) -1-oxo-4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-2-yl) -acetic acid, obtained in the foregoing Example 37) above; (1.50 g); in a mixture obtained by mixing 200.0 ml; 2N sodium hydroxide solution; 100.0 ml; tetrahydrofuran; and 100.0 ml; methanol, was stirred at room temperature; for 3.0 hours.

After the previous operation described above, the organic solvents were removed from the reaction mixture under reduced pressure; and the mixture was acidified with hydrochloric acid; extracted with ethyl acetate. After separation of the organic and aqueous phases, the organic layer was dried with magnesium sulfate; and evaporated.

The title compound was crystallized from acetone: petroleum ether; (bp 60.0-95.0 ° C).

Mp 183.0-187.0 ° C;

Example 39)

Preparation of (cis) -6-74- (3,4-dimethoxyphenyl) -1-oxo-4a, 5,6,7,8,8a-hexahydro-1H-phthalazin-2-yl / hexanoic acid (sodium salt)

The title compound was prepared from (cis) -4- (3,4-dimethoxyphenyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one; as a starting material obtained in the above-described Example 1); and 6-bromohexanoic acid, as described in Example 8 above); with the difference that instead of 6.0 mmol sodium hydride, 12.0 mmol was used.

After evaporation of the reaction mixture, the resulting residue was partitioned between aqueous sodium carbonate; and ethyl acetate. After separation of the aqueous and organic phases, the aqueous solution was acidified with hydrochloric acid, and extracted with ethyl acetate. After separation of the aqueous and organic phases, the organic layer was dried with magnesium sulfate, and evaporated. After purification of the residue by chromatography, eluting with ethyl acetate, the oil was dissolved in diethyl ether; and after adding a concentrated solution of sodium ethoxide to the resulting solution, the resulting precipitate was filtered off; and the desired compound was crystallized from a mixture of methanol and ether.

Mp: 140.0-143.0 ° C;

-29GB 293815 B6

Example 40)

Preparation of (cis) -6-74- (3,4-dimethoxyphenyl) -1-oxo-4a, 5,8,8a-tetrahydro-1H-phthalazin-2-yl-hexanoic acid

In an analogous manner to that described in the previous Example 39); was from (cis) -4- (3,4-dimethoxyphenyl) -4a, 5,8,8a-tetrahydro-2H-phthalazin-1-one; as a starting material obtained in the above-described Example 3); and 6-bromohexanoic acid, the title compound which is purified by chromatography; and crystallization from ether at minus 20.0 ° C.

Melting point: 97.0 to 99.0 ° C;

Example 41)

Preparation of (cis) -6- [4- (3,4-dimethoxyphenyl) -1-oxo-4a, 5,6,7,8,8a-hexahydro-1H-phthalazin-2-yl] -octanoic acid

Analogous to the procedure described above in Example 39); was from (cis) -4- (3,4-dimethoxyphenyl) -5a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one; as a starting material obtained in the above-described Example 1); and 8-bromooctanoic acid, the title compound was obtained, which was purified by chromatography.

Melting point: 90.0-91.0 ° C;

Example 42)

Preparation of (cis) -4- (3,4-dimethoxyphenyl) -2- (6-bromo-1-hexyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one

In an analogous manner to that described in Example 58); was from (cis) -4- (3,4-dimethoxyphenyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one; as a starting material; and obtained as described in Example 1) above; and 1,6-dibromohexane, the title compound which was purified by chromatography using ethyl acetate: petroleum ether; (bp 60.0-80.0 ° C); in a ratio of 1.0: 2.0; as an eluent, and which was crystallized from petroleum ether; (boiling point; (60.0-80.0 ° C)).

Mp 74.0-75.0 ° C;

Example 43)

Preparation of (cis) -4- (3,4-dimethoxyphenyl) -2- (6-amino-1-hexyl) -4a _J 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one fumarate

Solution, reconstituted 5.0 g; (cis) -4- (3,4-dimethoxyphenyl) -2- (6-bromo-1-hexyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one; as starting material obtained in the framework of the foregoing Example 42) described above; in a mixture prepared by mixing 200.0 ml of methanol; and 100.0 mL of tetrahydrofuran; saturated with gaseous ammonia; and the reaction mixture was allowed to stand; at room temperature for one week.

-30GB 293815 B6

Then the solvent was evaporated from the mixture; and the resulting residue was partitioned between aqueous sodium carbonate solution; and ethyl acetate. After separation of the organic and aqueous phases, the organic layer was evaporated; and the title compound was crystallized as a fumarate; a mixture of methanol; and ethyl acetate.

Melting point: 127.0 to 129.0 ° C;

Example 44)

Preparation of (cis) -4- (3,4-dimethoxyphenyl) -2- (4-aminomethyl-1-butyl) -4,5,6,7,8,8a-hexahydro-2H-phthalazin-1-one hemifumarate

In an analogous manner to that described in Example 46 below; was from (cis) -4- (3,4-dimethoxyphenyl) -2- (4-bromo-1-butyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one; as a starting material, and obtained in the context of Example 58 below); and methylamine; the title compound was obtained and purified by chromatography; and crystallized in the form of hemifumarate, from ethyl acetate.

Mp 108.0-111.0 ° C;

Example 45)

Preparation of (cis) -4- (3,4-dimethoxyphenyl) -2- (2-dimethylaminoethyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one fumarate

Analogous to the procedure described above in Example 8); was from (cis) -4- (3,4-dimethoxyphenyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one; as a starting material obtained in the above-described Example 1); and 2-bromoethyl-N, N-dimethylamine, hydrobromide; prepared title compound; with the difference that instead of 6.0 mmol sodium hydride, 12.0 mmol was used in the reaction.

The title compound was purified by chromatography, eluting with ethyl acetate; and crystallized in the form of a fumarate; from ether.

Mp 74.0-76.0 ° C;

Example 46)

Preparation of (cis) -4- (3,4-dimethoxyphenyl) -2- (4-dimethylamino-1-butyl) -4a, 5,6,7,8,8-hexahydro-2H-phthalazin-1-one fumarate.

A solution prepared by dissolving 2.0 g; (cis) -4- (3,4-dimethoxyphenyl) -2- (4-bromo-1-butyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one; as a starting material obtained in the context of Example 58 below); in a 30% dimethylamine solution; in ethanol, was allowed to stand at room temperature; for 18.0 hours.

Then the reaction mixture was evaporated; and the resulting residue was purified by chromatography, eluting with ethyl acetate, then recrystallized as fumarate from ether.

Mp: 119.0-121.0 ° C;

-31 GB 293815 B6

Example 47)

Preparation of (cis) -4- (3,4-dimethoxyphenyl) -2- (6-dimethylamino-1-hexyl) -4a, 5,6,7,8,8-hexahydro-2H-phthalazin-1-one oxalate

In an analogous manner to that described in the preceding Example 46); was from (cis) -4 (3,4-dimethoxyphenyl) -2- (6-bromo-1-hexyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one such as starting material; and obtained as described in Example 42) above; the title compound which was recrystallized from acetone; in the form of oxalate.

Melting point: 65.0 - 67.0 ° C;

Example 48)

Preparation of (cis) -4- (3,4-dimethoxyphenyl) -2- [4- (1-piperidyl) -1-butyl] -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one hydrochloride

In an analogous manner to that described in Example 46 above; was from (cis) -4- (3,4-dimethoxyphenyl) -2- (4-bromo-1-butyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one, as a starting material; obtained under Example 58) described below; the title compound was prepared except piperidine was used in the reaction instead of dimethylamine.

The title compound was purified by chromatography using ethyl acetate as eluent; and recrystallized, in the form of the hydrochloride; from diethyl ether.

Melting point: 63.0-68.0 ° C;

Example 49)

Preparation of (cis) -2- (N-methylpiperidin-4-yl) -4- (3,4-dimethoxyphenyl) -4a, 5,6,7,8,8ahexahydro-2H-phthalazin-1-one fumarate

Mixture prepared by mixing 10.0 mmol; (cis) -4- (3,4-dimethoxyphenyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one; as a starting material; and obtained as described in Example 1) above; further 10.0 mmol; 4-chloro-N-methylpiperidine hydrochloride; and 20.0 mmol; sodium hydride; in dimethylformamide, was heated at 120.0 ° C; for 150.0 hours.

At the end of the above operation, the reaction mixture was evaporated, and the resulting residue was purified by chromatography using ethyl acetate: triethylamine; (10: 1.0); as eluent; and thereafter, in the form of a fumarate; was recrystallized from tetrahydrofuran.

Melting point: 200.0 ° C; (with decomposition)

Example 50)

Preparation of (cis) -4- (3,4-dimethoxyphenyl) -2- (2-nitroxy-1-ethyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one hydrochloride

To a solution prepared by dissolving 10.0 mmol of (cis) -4- (3,4-dimethoxyphenyl) -2- (2-hydroxyl-ethyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazine -l-one; as a starting material, and obtained under Example 35 above); in 100.0 ml; dichloromethane, was added at 0 ° C; a mixture prepared by mixing 20.0 mmol of acetic anhydride; and 20.0 mmol of nitric acid.

-32GB 293815 Β6

After 30.0 minutes, 150.0 mL was added to the resulting reaction mixture; water, and the mixture was further worked up by separating the organic and aqueous layers; and the organic layer was dried with magnesium sulfate; and evaporated.

The title compound was recrystallized from ethyl acetate.

Mp: 139.0-140.0 ° C;

Example 51)

Preparation of (cis) -N, N-dimethyl-4- [4- (3,4-dimethoxyphenyl) -1-oxo-4a, 5,6,7,8,8a-hexahydro-1H-phthalazin-2-yl] -acetamide

To a mixture prepared by mixing 5.0 mmol; (cis) - [4- (3,4-Dimethoxyphenyl) -1-oxo-4a, 5,6,7,8,8a-hexahydro-1H-phthalazin-2-yl] acetamide

To a mixture prepared by mixing 5.0 mmol; (cis) - [4- (3,4-dimethoxyphenyl) -1-oxo-4a, 5,6,7,8,8a-hexahydro-1H-phthalazin-2-yl] acetic acid as starting material; and obtained as described in Example 38) above; and 5.0 mmol; triethylamine, in dichloromethane, was added at a temperature of minus 20.0 ° C; 5.0 mmol, ethyl chloroformate; and the resulting reaction mixture was stirred for 30.0 minutes.

At the end of the above operation, 6.0 mmol was added to the reaction mixture; dimethylammonium chloride; and 6.0 mmol; triethylamine, in dichloromethane; and the resulting reaction mixture was stirred at room temperature for 1.0 hour; and then aqueous sodium carbonate solution was added. After separation of the organic and aqueous phases, the organic layer was dried with magnesium sulfate; and evaporated.

After recrystallization from ethyl acetate; and diethyl ether to give the title compound.

Melting point: 142.0-145.0 ° C;

Example 52)

Preparation of (cis) -4- (3,4-dimethoxyphenyl) -2- (2-oxo-2-phenylethyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one

Analogous to the procedure described above in Example 8); was from (cis) -4- (3,4-dimethoxyphenyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one; as a starting material; and obtained as described in Example 1) above; and 2-bromoacetophenone, the desired title compound, which was purified by chromatography using ethyl acetate: petroleum ether; (bp 60.0-80.0 ° C); ratios 1.0: 3.0; as eluent; and crystallization from diethyl ether.

Melting point: 133.0-135.0 ° C;

-33GB 293815 B6

Example 53)

Preparation of (cis) -4- (3,4-dimethoxyphenyl) -2- [2- (2-methoxyphenyl) -oxoethyl-2-4a, 5,6,7,8,8a-hexahydro-2H-phthalazine-1- onu

To a solution prepared by dissolving 2.0 g; omega-bromo-2-methoxyacetophenone; in dimethylformamide; a mixture was added; obtained by mixing 2.0 g; (cis) -4- (3,4-dimethoxyphenyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one; as a starting material obtained in the above-described Example 1); and 1.0 equivalent; sodium ethoxide; in 30.0 ml of dimethylformamide.

After 30.0 minutes, an additional amount of omega-bromo-2-methoxyacetophenone was added in small portions to the resulting reaction mixture; (total 5.0 grams); and sodium ethoxide, such that the addition took place within 2.0 hours.

After the previous operation described above, the reaction mixture was evaporated; and the resulting residue was partitioned between water, and ethyl acetate. After separation of the organic and aqueous phases, the organic layer was dried with magnesium sulfate; and then evaporated.

The residue was purified by chromatography, eluting with dichloromethane; and crystallization from methanol; and the desired was obtained; the title compound.

Melting point: 93.0 to 96.0 ° C;

Example 54)

Preparation of (cis) -2- [2- (4-chlorophenyl) -2-oxoethyl] -4- (3,4-dimethoxyphenyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazine-1 -onu

Analogous to the procedure described above in Example 8); was from (cis) -4- (3,4-dimethoxyphenyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one; as a starting material, and obtained in the framework of Example 1 above); and omega-4-chloroacetophenone; to give the title compound which was recrystallized from methanol.

Melting point: 142.0-144.0 ° C;

Example 55)

Preparation of (cis) -4- (3,4-dimethoxyphenyl) -2- [2- (2-naphthyl) -2-oxoethyl] -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one

Analogous to the procedure described above in Example 8); was from (cis) -4- (3,4-dimethoxyphenyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one; as a starting material obtained in the above-described Example 1); and alpha-bromo-2'-acetophenone; prepared by chromatography using ethyl acetate: petroleum ether (60.0-80.0 ° C); (1.0: 3.0); as eluent; and crystallization from methanol, at a temperature of minus 20.0 ° C.

Mp: 89.0-90.0 ° C;

-34GB 293815 B6

Example 56)

Preparation of (cis) -4- (3,4-dimethoxyphenyl) -2-diphenylmethyl-4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one

Analogous to the procedure described above in Example 8); was from (cis) -4- (3,4-dimethoxyphenyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one; as a starting material obtained in the above-described Example 1); and diphenylchloromethane, to give the title compound, which was purified by chromatography using dichloromethane as eluent; and crystallization from methanol.

Melting point: 133.0-135.0 ° C;

Example 57)

Preparation of (cis) -4- (3,4-dimethoxyphenyl) -2- (3-phenoxy-1-propyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one

Analogous to the procedure described above in Example 8); was from (cis) -4- (3,4-dimethoxyphenyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one; as a starting material; obtained under Example 1 above); and 3-phenoxy-1-bromopropane; the title compound was obtained, which was purified by chromatography using dichloromethane; as eluent; and crystallization from petroleum ether; (bp 60.0-80.0 ° C).

Mp 78.0-81.0 ° C;

Example 58)

Preparation of (cis) -4- (3,4-dimethoxyphenyl) -2- (4-bromo-1-butyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one

To the mixture prepared by mixing 5.0 g; (cis) -4- (3,4-dimethoxyphenyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one; as a starting material obtained in the above-described Example 1); and 1.0g; sodium hydride; and dimethylformamide; 15.0 g was added; 1,4-dibromobutane; and the resulting reaction mixture was stirred for 5.0 hours.

After the previous operation described above, the solvent from the reaction mixture was evaporated; and the residue was partitioned between water, and ethyl acetate. After separation of the organic and aqueous phases, the solution was ethyl acetate; dried with sodium sulfate; and evaporated.

The residue was purified by chromatography using dichloromethane as eluent; to give the title compound.

Melting point: colorless oil. 1 H-NMR; (CDCl3):

1.20 - 1.97; (m .; 11H, 7 x cyclohexyl H, Br-C-CH ₂ -CH _2); 2.44 - 2.73; (m, 2H; 2 x cyclohexyl H); 2.88 - 3.15; (m, 1H; cyclohexyl H); 3.49; (t .; J = 6.00 Hz, 2H, _Br-CH2); 3.72 - 4.12; (m, 8H; N-CH3); 2x0-CH _3); 6.84; (d, J = 8.40 Hz; 1H, arom. H); 7.21; (dd; J = 2.00; 8.40 Hz; 1H; arom. H); 7.47; (d, J = 2.0 Hz; 1H, arom. H).

-35GB 293815 B6

Example 59)

Preparation of (cis) -4- (3,4-dimethoxyphenyl) -2-phenyl-4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one

Analogous to the procedure described above in Example 14); was from 2- (3,4-dimethoxybenzoyl) - [cis] -cyclohexanecarboxylic acid as starting material; and obtained under Example A) described below; and phenylhydrazine, to give the title compound, which was recrystallized from ethyl acetate: petroleum ether; (boiling point, 60.0 to 95.0 ° C); as a crystallizing agent.

Mp: 122.0-124.0 ° C;

Example 60)

Preparation of (cis) -4- (3,4-dimethoxyphenyl) -2-phenyl-4a, 5,8,8a-tetrahydro-2H-phthalazin-1-one

Analogously to Example 35 above; prepared from (cis) -2- (3,4-dimethoxybenzoyl) -1,2,3,6-tetrahydrobenzoic acid; as a starting material; and obtained under Example C); described below; and phenylhydrazine; prepared title compound; which was recrystallized from diethyl ether.

Mp: 134.0-135.0 ° C;

Example 61)

Preparation of (cis) -4- (3-ethoxy-4-methoxyphenyl) -2-phenyl-4α, 5,8,8α-tetrahydro-2H-phthalazin-1-one

Analogously to Example 35 above; was from (cis) -2- (3-ethoxy-4-methoxybenzoyl) -1,2,3,6-tetrahydrobenzoic acid as the starting material; and obtained under Example F); described below; and phenylhydrazine, to give the title compound which was at a temperature of minus 20.0 ° C; crystallized from diethyl ether.

Melting point: 97.0 to 99.0 ° C;

Example 62)

Preparation of (cis) -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-phenyl-4a, 5,8,8a-tetrahydro-2H-phthalazin-1-one

Analogously to Example 35 above; was from (cis) -2- (3-cyclopentyloxy-4-methoxybenzoyl) -1,2,3,6-tetrahydrobenzoic acid; as a starting material; and obtained under Example E); described below; and phenylhydrazine; to give the title compound which was recrystallized from methanol.

Mp: 134.0-135.0 ° C;

-36GB 293815 B6

Example 63)

Preparation of (cis) -4- (3,4-dimethoxyphenyl) -2- (2-ethylphenyl) -4a, 5,8,8a-tetrahydro-2H-phthalazin-1-one

Analogously to Example 35 above; was from (cis) -2- (3,4-dimethoxybenzoyl) -1,2,3,6-tetrahydrobenzoic acid; as a starting material; and obtained within the framework of Example C) described below; and 2-methylphenylhydrazine; ready prepared; the title compound which was recrystallized from methanol.

Mp: 144.0-145.0 ° C;

Example 64)

Preparation of (cis) -4- (3,4-dimethoxyphenyl) -2- (4-tert-butylphenyl) -4a, 5,8,8a-tetrahydro-2H-phthalazin-1-one

Analogously to Example 35 above; was from (cis) -2- (3,4-dimethoxybenzoyl) -1,2,3,6-tetrahydrobenzoic acid as the starting material; and obtained in the context of Example C) described below; and 4-tert-butylphenylhydrazine, prepared as desired; the title compound which was recrystallized from ethanol.

Melting point: 197.0 - 199.0 ° C;

Example 65)

Preparation of (cis) -4- (3,4-dimethoxyphenyl) -2- (2-chlorophenyl) -4a, 5,8,8a-tetrahydro-2H-phthalazin-1-one

Analogously to Example 35 above; was from (cis) -2- (3,4-dimethoxybenzoyl) -1,2,3,6-tetrahydrobenzoic acid; as starting material obtained in Example C) described below; and 4-chlorophenylhydrazine; to give the title compound which was recrystallized from methanol.

Mp: 131.0-134.0 ° C;

Example 66)

Preparation of (cis) -4- (3,4-dimethoxyphenyl) -2- (4-chlorophenyl) -4a, 5,8,8a-tetrahydro-2H-phthalazin-1-one

Analogously to Example 35 above; was from (cis) -2- (3,4-dimethoxybenzoyl) -1,2,3,6-tetrahydrobenzoic acid as a starting material; and obtained in the context of Example C) described below; and 2-chlorophenylhydrazine, the title compound is obtained.

Mp: 140.0-141.0 ° C;

-37GB 293815 B6

Example 67)

Preparation of (cis) -4- [4- (3,4-dimethoxyphenyl) -1-oxo-4a, 5,8,8a-tetrahydro-1H-phthalazin-2-yl] benzoic acid

Analogously to Example 35 above; was from (cis) -2- (3,4-dimethoxybenzoyl) -1,2,3,6-tetrahydrobenzoic acid as a starting material; and obtained in the context of Example C) described below; and 4-hydrazinobenzoic acid, prepared desired; the title compound which was recrystallized from ethyl acetate.

Mp: 198.0-199.0 ° C;

Example 68)

Preparation of (cis) -3- [4- (3,4-dimethoxyphenyl) -1-oxo-4a, 5,8,8a-tetrahydro-1H-phthalazin-2-yl] benzoic acid

In an analogous manner to that described in Example 35 above; was from (cis) -2- (3,4-dimethoxybenzoyl) -1,2,3,6-tetrahydrobenzoic acid; as a starting material, and obtained under Example C) described below; and 3-hydrazinobenzoic acid, the title compound which was recrystallized from ethyl acetate: petroleum ether (b.p. 60.0-80.0 ° C);

Mp: 185.0-186.0 ° C;

Example 69)

Preparation of (cis) -n-propyl-4- [4- (3,4-dimethoxyphenyl) -1-oxo-4a, 5,8,8a-tetrahydro-1H-phthalazin-2-yl] -benzoate

Solution prepared by dissolving 1,0 g; (cis) -4- [4- (3,4-dimethoxyphenyl) -1-oxo-4a, 5,8,8a-tetrahydro-1H-phthalazin-2-yl] benzoic acid starting material; and obtained as described in Example 67 above); and 1.0 g; p-toluenesulfonic acid; in 100.0 ml; 1-propanol, was heated to reflux; for 18.0 hours.

After evaporation of the solvent from the reaction mixture, it was desired; the title compound; crystallized from methanol.

Mp: 100.0-101.0 ° C;

Example 70)

Preparation of (cis) -4- (3,4-dimethoxyphenyl) -2- [4- (2-hydroxyethyl) phenyl] -4a, 5,8,8a-tetrahydro-2H-phthalazin-1-one

Analogously to Example 35 above; was from (cis) -2- (3,4-dimethoxybenzoyl) -1,2,3,6-tetrahydrobenzoic acid as the starting material; obtained under Example C) described below; and 2- (4-hydrazinophenyl) ethanol, prepared as desired; the title compound which was crystallized from diethyl ether.

Mp: 137.0-139.0 ° C;

-38GB 293815 B6

Example 71)

Preparation of (cis) -4- [4- (3,4-dimethoxyphenyl) -1-oxo-4a, 5,8,8a-tetrahydro-1H-phthalazin-2-yl] phenylacetic acid

Analogously to Example 35 above; was from (cis) -2- (3,4-dimethoxybenzoyl) -1,2,3,6-tetrahydrobenzoic acid; as a starting material; and obtained under Example C); described below; and 4-hydrazinophenylacetic acid, prepared desired; the title compound which was crystallized from diethyl ether.

Mp: 162.0 ° C;

Example 72)

Preparation of (cis) -4- (3,4-dimethoxyphenyl) -2- (4-nitrophenyl) -4a, 5,8,8a-tetrahydro-2H-phthalazin-1-one

In an analogous manner to that described in Example 35 above; was from (cis) -2- (3,4-dimethoxybenzoyl) -1,2,3,6-tetrahydrobenzoic acid; as starting material obtained in Example C) described below; and 4-nitrophenylhydrazine, prepared as desired; the title compound, which was crystallized from methanol.

Melting point: 179.0-182.0 ° C;

Example 73)

Preparation of (cis) -4- (3,4-dimethoxyphenyl) -2- (4-aminosulfonylphenyl) -4a, 5,8,8a-tetrahydro-2H-phthalazin-1-one

From 2.0 g; 4-sulfonamidophenylhydrazine; and 3.0 g; (cis) -2- (3,4-dimethoxybenzoyl) -1,2,3,6-tetrahydrobenzoic acid starting material; obtained under Example C below; was analogous to that described in Example 35 above; after evaporation of the solvent from the reaction mixture, the title compound is obtained so that the residue is crystallized from methanol; and recrystallized from tetrahydrofuran; and petroleum ether; (bp 60.0-80.0 ° C).

Melting point: 181.0 - 183.0 ° C;

Example 74)

Preparation of (cis) -4- (3,4-dimethoxyphenyl) -2- (4-aminophenyl) -4a, 5,8,8a-tetrahydro-2H-phthalazin-1-one

Mixture prepared by mixing 35.0 mmol; (cis) -4- (3,4-dimethoxyphenyl) -2- (4-nitrophenyl) -4a, 5,8,8a-tetrahydro-2H-phthalazin-1-one; as the starting material obtained in the above-described Example 72); and 15.0 g; irons; in a mixture obtained by mixing 300.0 ml of ethanol; and 80.0 ml water; at 65.0 ° C; was treated with 10.0 ml over 45.0 minutes; 2N hydrochloric acid solution.

After the previous operation described above, the reaction mixture was filtered; the solvent was evaporated; and the resulting residue was washed with ethyl acetate.

-39GB 293815 B6

The title compound was obtained.

Mp 183.0-185.0 ° C;

Example 75)

Preparation of (cis) -4- (3,4-dimethoxyphenyl) -2- [4- (4-methylphenylsulfonamide) -phenyl] -4a, 5,8,8a-tetrahydro-2H-phthalazin-1-one

To a solution prepared by dissolving 10.0 mmol; (cis-4- (3,4-dimethoxyphenyl) -2- (4-aminophenyl-4a, 5,8,8a-tetrahydro-2H-phthalazin-1-one; obtained in the preceding; Example 74 above); 100.0 ml of pyridine, 20.0 mmol of p-toluenesulfonyl chloride were added and the resulting reaction mixture was allowed to stand at room temperature overnight.

After the previous operation described above, the solvent from the reaction mixture was evaporated; and the resulting residue was partitioned between aqueous sodium carbonate solution; and ethyl acetate. After separation of the organic and aqueous phases, the organic layer was dried with magnesium sulfate; and evaporated.

After crystallization from methanol; the desired was obtained; the title compound.

Melting point: 229.0-230.0 ° C;

Example 76)

Preparation of (cis) -5- {4- / 4- (3,4-dimethoxyphenyl) -1-oxo-4a, 5,8,8a-tetrahydrophthalazin-2-yl / phenyl} -2-ethyltetrazole

Analogously to Example 35 above; prepared from 2- (3,4-dimethoxybenzoyl) -1,2,3,6-tetrahydrobenzoic acid as starting material; and obtained in the context of Example C) described below; and 4- (3-ethyltetrazol-5-yl) -phenylhydrazine; the title compound, which was crystallized from diethyl ether.

Mp: 135.0-137.0 ° C;

Example 77)

Preparation of (cis) -5-2-benzyltetrazole

In an analogous manner to that described in Example 35 above; was from (cis) -2- (3,4-dimethoxybenzoyl) -1,2,3,6-tetrahydrobenzoic acid; and 2-benzyl-5- (4-hydrazinophenyl) -tetrazole as starting materials obtained in Example C); and Example N); described below; the title compound which was crystallized from methanol.

Mp: 100.0-102.0 ° C;

-40GB 293815 B6

Example 78)

Preparation of (cis) -2-benzyl-4- (3,4-dimethoxyphenyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one

To a suspension prepared from 5.0 mmol of (cis) -4- (3,4-dimethoxyphenyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one; as a starting material; and obtained in Example 1); described above; in about 40.0 ml; dimethylformamide was added under a nitrogen atmosphere; and at room temperature; 6.0 mmol; 60% suspension of sodium hydride in mineral oil; and the resulting reaction mixture was stirred for 30.0 minutes.

After the previous operation, 7.0 mmol of benzyl chloride was added to the reaction mixture; and the resulting mixture was stirred for an additional 4.0 hours. After evaporation of the solvent, the resulting residue was partitioned between ethyl acetate; and water, and after separation of the organic and aqueous phases, the organic layer was dried with magnesium sulfate; and evaporated. The residue, in the desired form, the title compound; was crystallized from methanol.

Melting point: 117.0-118.0 ° C;

Example 79)

Preparation of (trans) -2-benzyl-4- (3,4-dimethoxyphenyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one

A mixture prepared by mixing 10.0 mmol of 2- (3,4-dimethoxybenzyl) - (trans) -cyclohexane carboxylic acid; as starting material obtained in Example B) described below; and 10.0 mmol of benzylhydrazine hydrochloride; in 100.0 ml; toluene, was heated to reflux in a Dean-Stark apparatus; for 8.0 hours.

After completion of the above operation, the reaction mixture was cooled to room temperature; and after washing with an aqueous solution of sodium carbonate; dried with magnesium sulfate; and then evaporated.

The resulting residue was purified by column chromatography; using ethyl acetate: petroleum ether; (bp 60.0-80.0 ° C); in a ratio of 1: 3.0; and the title compound obtained was crystallized from diethyl ether.

Mp: 86.0-88.0 ° C;

Example 80)

Preparation of (cis) -2-benzyl-4- (3,4-dimethoxyphenyl) -4a, 5,8,8a-tetrahydro-2H-phthalazin-1-one

In an analogous manner to that described in Example 78 above; was from (cis) -4- (3,4-dimethoxyphenyl) -4a, 5,8,8a-tetrahydro-2H-phthalazin-1-one; as a starting material obtained in the above-described Example 3); and benzyl chloride; to obtain the title compound, which was purified by the title compound, which was purified by chromatography; using ethyl acetate: petroleum ether; (bp 60.0-80.0 ° C); prepared in ratios of 1: 3.0; as eluent; and then crystallized from diethyl ether.

Melting point: 133.0-135.0 ° C;

-41 CZ 293815 B6

Example 81)

Preparation of (cis) -2-benzyl-4- (3-cyclopentyloxy-4-methoxyphenyl) -4a, 5,6,7,8a-hexahydro-2H-phthalazin-1-one

Analogous to the procedure described above in Example 78); was from (cis) -4- (3-cyclopentyloxy-4-methoxyphenyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one; as a starting material, and obtained as described in Example 4 above); and benzyl chloride; the title compound was obtained and purified by chromatography; using a mixture of petroleum ether; (bp 60.0-95.0 ° C); and ethyl acetate; in 4: 1 ratios; as eluent; and crystallization from petroleum ether; (bp 60.0-95.0 ° C); and ethyl acetate.

Mp: 91.0-92.0 ° C;

Example 82)

Preparation of (cis) -2-benzyl-4- (3,4-diethoxyphenyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one

Analogous to the procedure described above in Example 78); was from (cis) -4- (3,4-diethoxyphenyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one; as a starting material; obtained under Example 7) described above; and benzyl chloride; ready prepared; the title compound, which was crystallized from petroleum ether; (bp 60.0-95.0 ° C).

Mp: 91.0-92.0 ° C;

Example 83)

Preparation of (cis) -4- [4- (3,4-dimethoxyphenyl) -1-oxo-4a, 5,6,7,8,8a-hexahydro-1H-phthalazin-2-ylmethyl] -benzoic acid

From (cis) -4- (3,4-dimethoxyphenyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one; as a starting material; obtained in Example 1); described above; and 4-chloromethylbenzoic acid, the title compound was prepared as described in Example 78 above; except that instead of 6.0 mmol sodium hydride, 12.0 mmol was used in the reaction. Another procedure involved evaporation of the reaction mixture; and shaking the resulting residue between aqueous sodium carbonate solution; and ethyl acetate. After separation of the aqueous and organic phases, the aqueous solution was acidified with hydrochloric acid; and extracted subsequently with ethyl acetate. After separation of the organic and aqueous phases, the organic layer was dried with magnesium sulfate; and evaporated.

The title compound was purified by chromatography using ethyl acetate; as eluent; and then crystallized from diethyl ether.

Mp: 135.0-139.0 ° C;

Example 84)

Preparation of (cis) -4- [4- (3-ethoxy-4-methoxyphenyl) -1-oxo-4a, 5,8,8a-tetrahydro-1H-phthalazin-2-ylmethyl] -benzoic acid as hemietherate

In an analogous manner to that described in Example 83 above; was from (cis) -4- (3-ethoxy-4-methoxyphenyl) -4a, 5,8,8a-tetrahydro-2H-phthalazin-1-one; as starting material obtained in the framework of the above-described Example 6); and 4-chloromethylbenzoic acid; ready prepared;

The title compound was crystallized from diethyl ether: petroleum ether; (bp 60.0-80.0 ° C).

Mp: 132.0-133.0 ° C;

Example 85)

Preparation of (cis) -4- [4- (3,4-diethoxyphenyl} -1-oxo-4a, 5,6,7,8,8a-hexahydro-1H-phthalazin-2-ylmethyl) -benzoic acid

In an analogous manner to that described in Example 83 above; was from (cis) -4- (3,4-diethoxyphenyl) -4a, 5,6,7,8a-hexahydro-2H-phthalazin-1-one; as a starting material; and obtained as described in Example 7) above; and 4-chloromethylbenzoic acid, prepared desired; the title compound, which was purified by chromatography using dichloromethane; as eluent; and crystallization from diethyl ether.

Mp 152.0-154.0 ° C;

Example 86)

Preparation of (cis) -4- [4- (3-cyclopentyloxy-4-methoxyphenyl) -1-oxo-4a, 5,6,7,8,8a-hexahydro-1H-phthalazin-2-ylmethyl) -benzoic acid

In an analogous manner to that described in Example 83 above; was from (cis) -4- (3-cyclopentyloxy-4-methoxyphenyl) -4a, 5,8,8a-hexahydro-2H-phthalazin-1-one; as a starting material; and obtained as described in Example 4) above; and 4-chloromethylbenzoic acid; ready prepared; the title compound, which was crystallized from ethyl acetate.

Mp: 189.0-190.0 ° C;

Example 87)

Preparation of (cis) -4- [4- (3,4-dimethoxyphenyl) -1-oxo-4a, 5,8,8a-tetrahydro-1H-phthalazin-2-ylmethyl] -benzoic acid

In an analogous manner to that described in Example 83 above; was from (cis) -4- (3,4-dimethoxyphenyl) -4a, 5,8,8a-tetrahydro-2H-phthalazin-1-one as a starting material; and obtained under Example 3); described above; and 4-chloromethylbenzoic acid, prepared desired; the title compound, which was crystallized from ethyl acetate.

Mp: 192.0-193.0 ° C;

Example 88)

Preparation of (cis) -3- [4- (3,4-dimethoxyphenyl) -1-oxo-4a, 5,6,7,8,8a-hexahydro-1H-phthalazin-2-ylmethyl] -benzoic acid

In an analogous manner to that described in Example 83 above; was from (cis) -4- (3,4-dimethoxyphenyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one as the starting material obtained in Example 1); described above; and 3-bromomethylbenzoic acid, prepared desired; in the title

Said compound which has been purified by chromatography using ethyl acetate; as eluent; and crystallization from diethyl ether.

Mp: 133.0-136.0 ° C;

Example 89)

Preparation of (cis) -4- [4- (3,4-dimethoxyphenyl) -1-oxo-4a, 5,6,7,8,8a-hexahydro-1H-phthalazin-2-ylmethyl] -phenylacetic acid

In an analogous manner to that described in Example 83 above; starting from (cis) -4- (3,4-dimethoxyphenyl) -4a, _5,6,7,8), 8a-hexahydro-2H-phthalazin-l-one as a starting material; and obtained in Example 1); described above; and 4-chloromethylphenylacetic acid, prepared desired; the title compound, which was purified by chromatography using ethyl acetate; as eluent; and crystallization from diethyl ether.

Mp: 164.0-166.0 ° C;

Example 90)

Preparation of (cis) -4- (3,4-dimethoxyphenyl) -2- (2-methoxybenzyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one

Analogous to the procedure described above in Example 78); was from (cis) -4- (3,4-dimethoxyphenyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one starting material; and obtained in Example 1); described above); and 2-methoxybenzyl chloride, the title compound, which was purified by chromatography, eluting with dichloromethane; and crystallization from diethyl ether at a temperature of minus 20.0 ° C.

Melting point: 96.0 to 99.0 ° C;

Example 91)

Preparation of (cis) -4- (3,4-dimethoxyphenyl) -2- (3-methoxybenzyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one

Analogous to the procedure described above in Example 78); was from (cis) -4- (3,4-dimethoxyphenyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one as the starting material obtained in the above-described Example 1) ; and 3-methoxybenzyl chloride; the title compound was obtained, which was crystallized from methanol.

Mp 115.0 ° C;

Example 92)

Preparation of (cis) -4- (3,4-dimethoxyphenyl) -2- (4-methoxybenzyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one

Analogous to the procedure described above in Example 78); it was from (cis) -4- (3,4-dimethoxyphenyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one as the starting material obtained in frame-44EN 293815 B6 ci Example 1); described above; and 4-methoxybenzyl chloride, prepared as desired; the title compound which was crystallized from diethyl ether.

Mp: 77.0-78.0 ° C;

Example 93)

Preparation of (cis) -4- (3,4-dimethoxyphenyl) -2- (3,5-dimethoxybenzyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one

Analogous to the procedure described above in Example 78); was from (cis) -4- (3,4-dimethoxyphenyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one starting material; obtained under Example 1 above); and 3,5-dimethoxybenzyl chloride, prepared as desired; the title compound which was purified by chromatography using dichloromethane as eluent; and crystallization from methanol.

Mp: 114.0-117.0 ° C;

Example 94)

Preparation of (cis) -4- (3,4-dimethoxyphenyl) -2- (2-trifluoromethylbenzyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one

Analogous to the procedure described above in Example 78); z was (cis-4- (3,4-dimethoxyphenyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one as the starting material obtained in the above-described Example 1); and 2-trifluoromethylbenzyl chloride, to give the title compound, which was purified by chromatography; eluting with dichloromethane; and crystallization from petroleum ether; (bp 60.0-95.0 ° C).

Mp: 87.0-88.0 ° C;

Example 95)

Preparation of (cis) -2- (2-chlorobenzyl) -4- (3,4-dimethoxyphenyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one

Analogous to the procedure described above in Example 78); was from (cis) -4- (3,4-dimethoxyphenyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one as the starting material obtained in the above-described Example 1) ; and 2-chlorobenzyl chloride, the title compound; which was purified by chromatography using dichloromethane as eluent; and crystallization from petroleum ether; (bp 60.0-95.0 ° C).

Melting point: 101.0-104.0 ° C;

Example 96)

Preparation of (cis) -4- (3,4-dimethoxyphenyl) -2- (4-hydroxybenzyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one

From (cis) -4- (3,4-dimethoxyphenyl) -2- (4-benzyloxybenzyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one as a starting material Example 122; was

By catalytic debenzylation in ethanol, using 5% palladium on charcoal, the desired one was prepared; the title compound which was crystallized from diethyl ether.

Melting point: 177.0-179.0 ° C;

Example 97)

Preparation of (cis) -4- (3,4-dimethoxyphenyl) -2- (2-hydroxybenzyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one

In an analogous manner to that described in the preceding Example 96); was from (cis) -4- (3,4-dimethoxyphenyl) -2- (2-benzyloxybenzyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one; as starting material obtained in the context of Example 126 below); using catalytic debenzylation; ready prepared; the title compound.

Mp: 132.0-133.0 ° C;

Example 98)

Preparation of methyl (cis) -4- (3,4-dimethoxyphenyl) -1-oxo-4a, 5,6,7,8,8a-hexahydro-1H-phthalazin-2-ylmethyl-benzoate

To a solution prepared by dissolving 1.0 g; (cis) -4- [4- (3,4-dimethoxyphenyl) -1-oxo4a, 5,6,7,8,8a-hexahydro-1H-phthalazin-2-ylmethyl] -benzoic acid as starting material ; and obtained as described in Example 83 above); in methanol, was added slowly, at a temperature of minus 20.0 ° C; 3.0 ml; thionyl chloride.

After completion of the above operation, the resulting reaction mixture was stirred at room temperature for 6.0 hours; and then evaporated. After recrystallization of the residue from diethyl ether, at a temperature of minus 20.0 ° C; the desired was obtained; the title compound.

Melting point: 90.0-92.0 ° C;

Example 99)

Preparation of (cis) -4- (3,4-dimethoxyphenyl) -2- (2-pyridyl) -4a, 5,8,8a-tetrahydro-2H-phthalazin-1-one

Analogously to Example 35 above; was from (cis) -2- (3,4-dimethoxybenzoyl) -1,2,3,6-tetrahydrobenzoic acid as a starting material; and obtained in the context of Example C) described below; and 2-pyridylhydrazine, to give the title compound, which was purified by chromatography, eluting with ethyl acetate; and recrystallization from ethyl acetate: diethyl ether.

Melting point: 147.0-148.0 ° C;

-46GB 293815 B6

Example 100)

Preparation of (cis) -4- (3,4-dimethoxyphenyl) -2- (2-pyridylmethyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one

In an analogous manner to that described in Example 105); was from (cis) -4- (3,4-dimethoxyphenyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one starting material; and obtained as described in Example 1) above; and 2-picolyl chloride, hydrochloride; the title compound was obtained, which was recrystallized from diethyl ether.

Mp 181.0-182.0 ° C;

Example 101)

Preparation of (cis) -4- (3,4-dimethoxyphenyl) -2- (2-pyridylmethyl) -4a, 5,8,8a-tetrahydro-2H-phthalazin-1-one

In an analogous manner to that described in Example 105); was from (cis) -4- (3,4-dimethoxyphenyl) -4a, 5,8,8a-tetrahydro-2H-phthalazin-1-one as a starting material; and obtained in the framework of the above-described Example 3); and 2-picolyl chloride, hydrochloride, prepared as desired; the title compound which was recrystallized from diethyl ether.

Mp: 146.0-147.0 ° C;

Example 102)

Preparation of (cis) -4- (3,4-dimethoxyphenyl) -2- (3-pyridylmethyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one hydrochloride

In an analogous manner to that described in Example 105); was from (cis) -4- (3,4-dimethoxyphenyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one; as a starting material obtained in the above-described Example 1); and 3-picolyl chloride, hydrochloride, the title compound, which was purified by chromatography using dichloromethane as eluent; and crystallization from diethyl ether; in the form of the hydrochloride.

Mp: 192.0-195.0 ° C;

Example 103)

Preparation of (cis) -4- (3,4-dimethoxyphenyl) -2- (3-pyridylmethyl) -4a, 5,8,8a-tetrahydro-2H-phthalazin-1-one

In an analogous manner to that described in Example 105); was from (cis) -4- (3,4-dimethoxyphenyl) -4a, 5,8,8a-tetrahydro-2H-phthalazin-1-one as a starting material; and obtained in the framework of the above-described Example 3); and 3-picolyl chloride, hydrochloride, the title compound, which was purified by chromatography, eluting with ethyl acetate; and crystallization from diethyl ether.

Melting point: 117.0-120.0 ° C;

-47GB 29381S B6

Example 104)

Preparation of (cis) -4- (3,4-dimethoxyphenyl) -2- (4-pyridylmethyl) -4a, 5,8,8a-tetrahydro-2H-phthalazin-1-one

In an analogous manner to that described in Example 105); was from (cis) -4- (3,4-dimethoxyphenyl) -4a, 5,8,8a-tetrahydro-2H-phthalazin-1-one, as a starting material, obtained as described in Example 3 above); and 4-picolyl chloride, hydrochloride; the title compound was obtained, which was purified by chromatography using ethyl acetate as eluent; and crystallization from diethyl ether.

Mp 121.0-124.0 ° C;

Example 105)

Preparation of (cis) -4- (3,4-dimethoxyphenyl) -2- (4-pyridylmethyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one

Analogous to the procedure described above in Example 78); was from (cis) -4- (3,4-dimethoxyphenyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one as a starting material and obtained as described in Example 1 above. ); and 4-picolyl chloride, hydrochloride, the title compound; with the difference that instead of 6.0 mmol sodium hydride, 12.0 mmol was used in the reaction.

The title compound was purified by chromatography using dichloromethane as eluent; and crystallization from diethyl ether.

Mp: 87.0-89.0 ° C;

Example 106)

Preparation of (cis) -4- (3,4-dimethoxyphenyl) -2- (2-indanyl) -4a, 5,8,8a-tetrahydro-2H-phthalazin-1-one

Analogously to Example 35 above; was from (cis) -2- (3,4-dimethoxybenzoyl) -1,2,3,6-tetrahydrobenzoic acid; as a starting material; and obtained in the context of Example C) described below; and 2-indanylhydrazine, prepared desired; the title compound which was recrystallized twice from methanol.

Mp: 163.0-164.0 ° C;

Example 107)

Preparation of (cis) -4- (3,4-dimethoxyphenyl) -2- (1,4-benzodiazin-2-yl) -4a, 5,8,8a-tetrahydro-2H-phthalazin-1-one

Analogously to Example 35 above; was from (cis) -2- (3,4-dimethoxybenzoyl) -1,2,3,6-tetrahydrobenzoic acid; as starting material obtained in Example C) described below; and 2-hydrazine-1,4-benzodiazine, the title compound, which was purified by chromatography; and recrystallization from diethyl ether.

Mp: 154.0-156.0 ° C;

-48GB 293815 B6

Example 108)

Preparation of (cis) -4- (3,4-dimethoxyphenyl) -2- (2-benzothiazolyl) -4a, 5,8,8a-tetrahydro-2H-phthalazin-1-one

Analogously to Example 35 above; was from (cis) -2- (3,4-dimethoxybenzoyl) -1,2,3,6-tetrahydrobenzoic acid; as a starting material; and obtained in the context of Example C) described below; and 2-hydrazinobenzothiazole, the title compound, which was purified by crystallization, using ethyl acetate: petroleum ether; (bp 60.0-80.0 ° C).

Melting point: 176.0-177.0 ° C;

Example 109)

Preparation of (cis) -4- (3,4-dimethoxyphenyl) -2- (2-methylthiazol-4-yl-4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one)

Analogous to the procedure described above in Example 78); was from (cis) -4- (3,4-dimethoxyphenyl) -4a, 5,6,7,8,8a-tetrahydro-2H-phthalazin-1-one as the starting material obtained in the above-described Example 1) ; and 4-chloromethyl-2-methylthiazole, prepared desired; the title compound, which was crystallized from ethyl acetate.

Mp: 135.0-137.0 ° C;

Example 110)

Preparation of (cis) -2- (Benzotriazol-1-ylmethyl) -4- (3,4-dimethoxyphenyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one

In an analogous manner to that described in Example 78 above; was from (cis) -4- (3,4-dimethoxyphenyl) -4a, 5,6,7,8,8a-tetrahydro-2H-phthalazin-1-one as the starting material obtained in the above-described Example 1) ; and 1-bromomethylbenzotriazole, the title compound prepared; except that sodium ethoxide was used in the reaction instead of sodium hydride; and the aforementioned desired compound was purified by chromatography using ethyl acetate: petroleum ether; (bp 60.0-95.0 ° C); 1: 2.0); and crystallization from methanol.

Mp: 173.0-178.0 ° C;

Example 111)

Preparation of (cis) -4- (3,4-dimethoxyphenyl) -2- (2-phenylethyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one

Analogous to the procedure described above in Example 78); was from (cis) -4- (3,4-dimethoxyphenyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one as the starting material obtained in the above-described Example 1) ; and 2-bromoethylbenzene, prepared as desired; the title compound, which was purified by chromatography, using ethyl acetate: petroleum ether; (bp 60.0-95.0 ° C); in a ratio of 1: 3.0; as eluent; and crystallization from methanol.

-49GB 293815 B6

Mp: 99.0-100.0 ° C;

Example 112)

Preparation of (cis) -4- (3,4-dimethoxyphenyl) -2- (2-bromoethyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one hydrochloride

To a solution prepared by dissolving 25.0 mmol; triphenylphosphine; in 50.0 ml; dichloromethane, was at 0 ° C; and under a nitrogen atmosphere, first add the solution obtained by dissolving 25.0 mmol; bromine; in 10.0 ml; dichlomethane; and then a solution, 25 mmol, obtained by dissolving (cis) -4- (3,4-dimethoxyphenyl) -2- (2-hydroxy-1-ethyl) -4a, 5,6,7,8,8a-hexahydro-2H- phthalazinone; (obtained under Example 35 above); in 25.0 ml; dichloromethane.

After completion of the above operation, the reaction mixture was stirred at room temperature for 2.0 hours; and then; after washing with aqueous sodium carbonate solution, it was dried with magnesium sulfate; and evaporated.

The title compound obtained; was recrystallized from methanol.

Mp: 134.0-136.0 ° C;

Example 113)

Preparation of (cis) -4- (3,4-dimethoxyphenyl) -2- [2- (1-imidazolyl) ethyl] -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one hydrochloride

Solution prepared by dissolving 2,0 g; (cis) -4- (3,4-dimethoxyphenyl) -2- (2-bromoethyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one hydrochloride obtained above, Example 112) described above; and 3.0 g; The imidazole, in methanol, was allowed to stand at room temperature for 18.0 hours.

After the above operation was completed, the solvent was evaporated from the reaction mixture; and the resulting residue was partitioned between water, and ethyl acetate. After separation of the organic and aqueous phases, the organic layer was dried with magnesium sulfate; and evaporated.

The residue was dissolved in ethyl acetate; and the resulting solution was filtered through silica. The title compound was crystallized from tetrahydrofuran; in the form of the hydrochloride.

Mp: 198.0-199.0 ° C;

Example 114)

Preparation of (cis) -4- (3,4-dimethoxyphenyl) -2- (4-bromo-1-butyl) -4a, 5,8,8a-tetrahydro-2H-phthalazin-1-one

Analogous to the procedure described above in Example 58); was from (cis) -2- (3,4-dimethoxybenzoyl) -1,2,3,6-tetrahydrobenzoic acid as a starting material; and obtained in the context of Example C) described below; and 1,4-dibromobutane, prepared as desired; the title compound.

Melting point: 105.0-106.0 ° C;

-50EN 293815 B6

Example 115)

Preparation of (cis) -4- (3,4-dimethoxyphenyl) -2- [4- (1-imidazolyl-1-butyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one hydrochloride

Analogous to the procedure described above in Example 113); was from (cis) -4- (3,4-dimethoxyphenyl) -2- (4-bromo-1-butyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one, as starting material obtained in the framework of Example 58 above); to obtain the title compound.

Melting point: 210.0-212.0 ° C;

Example 116)

Preparation of (cis) -4- (3,4-dimethoxyphenyl) -2- [4- (1-imidazolyl) -1-butyl] -4a, 5,8,8a-tetrahydro-2H-phthalazin-1-one hydrochloride

Analogous to the procedure described above in Example 113); was from (cis) -4- (3,4-dimethoxyphenyl) -2- (4-bromo-1-butyl) -4a, 5,8,8a-tetrahydro-2H-phthalazin-1-one; as a starting material; and obtained under Example 114 above); and imidazole, the desired title compound; by the process of evaporating the reaction mixture; and the resulting residue was dissolved in 2N hydrochloric acid solution.

After extraction with dichloromethane, and drying over magnesium sulfate, the solvent was evaporated; and the residue was crystallized; using ethyl acetate.

Mp: 192.0-194.0 ° C;

Example 117)

Preparation of (cis) -4- (3,4-dimethoxyphenyl) -2- (6-bromo-1-hexyl) -4a, 5,8,8a-tetrahydro-2H-phthalazin-1-one

Analogous to the procedure described above in Example 58); was from (cis) -2- (3,4-dimethoxybenzoyl) -1,2,3,6-tetrahydrobenzoic acid; as a starting material; obtained under Example C) described below; and 1,6-dibromohexane; the title compound.

Mp 55.0 - 56.0 ° C;

Example 118)

Preparation of (cis) -4- (3,4-dimethoxyphenyl) -2- [6- (1-imidazolyl) -1-hexyl] -4a, 5,8,8a-tetrahydro-2H-phthalazin-1-one hydrochloride

Analogous to the procedure described above in Example 113); was from (cis) -4- (3,4-dimethoxyphenyl) -2- (6-bromo-1-hexyl) -4a, 5,8,8a-tetrahydro-2H-phthalazin-1-one; as a starting material obtained in the framework of the above-described Example 117); and imidazole; the title compound was obtained and purified by chromatography; and crystallized as the hydrochloride; from tetrahydrofuran.

Melting point: 183.0 ° C;

-51 CZ 293815 B6

Example 119)

Preparation of (cis) -2- [6- (2-benzimidazole) -1-hexyl] -4- (3,4-dimethoxyphenyl) -4a, 5,8,8a-tetrahydro-2H-phthalazin-1-one hydrochloride

Analogous to the procedure described above in Example 113); was from (cis) -4- (3,4-dimethoxyphenyl) -2- (6-bromo-1-hexyl) -4a, 5,8,8a-tetrahydro-2H-phthalazin-1-one as a starting material, obtained as described in Example 117 above); and benzimidazole to give the title compound which was purified by chromatography; eluting with ethyl acetate; and crystallized as the hydrochloride.

Mp 67.0-70.0 ° C;

Example 120)

Preparation of (cis) -N- {6- [4- (3,4-Dimethoxyphenyl) -1-oxo-4a, 5,8,8a-tetrahydrophthalazin-2-yl / hexyl} -phthalimide

Mixture prepared by mixing 10.0 g; (cis) -4- (3,4-dimethoxyphenyl) -2- (5-bromo-1-hexyl) -4a, 5,8,8a-tetrahydro-2H-phthalazin-1-one; obtained as described in Example 117 above); further 10.0 g; phthalimide; and 10.0 g; potassium carbonate; in dimethylformamide, was heated at 100.0 ° C; for 5.0 hours.

Upon completion of the foregoing operation, the reaction mixture was diluted with water; and extracted with ethyl acetate. After separation of the organic and aqueous phases, the organic layer was dried with magnesium sulfate; and evaporated.

The resulting residue was purified by chromatography using dichloromethane as eluent; and crystallized from ethyl acetate: diethyl ether; to give the title compound.

Melting point: 104.0 - 105.0 ° C;

Example 121)

Preparation of (cis) -4- (3,4-dimethoxyphenyl) -2- (3-phenyl-2- (trans) -propenyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazine-1 -onu

Analogous to the procedure described above in Example 78); was from (cis) -4- (3,4-dimethoxyphenyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one as a starting material; and obtained as described in Example 1) above; and 3-phenyl-2- (trans) -propenyl chloride, prepared as desired; the title compound which was purified by chromatography; eluting with dichloromethane; and crystallization from diethyl ether; at minus 20.0 ° C.

Mp 76.0-79.0 ° C;

-52EN 293815 B6

Example 122)

Preparation of (cis) -4- (3,4-dimethoxyphenyl) -2- (4-benzyloxybenzyl) -4a, 5 _J 6,7,8,8a-hexahydro-2H-phthalazin-l-one

Analogous to the procedure described above in Example 78); was from (cis) -4- (3,4-dimethoxyphenyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one; as a starting material; and obtained as described in Example 1) above; and 4-benzyloxybenzyl chloride, prepared as desired; the title compound, which was purified by chromatography using dichloromethane as eluent; and which was isolated as a colorless, oily consistency, 1 H-NMR (CDCl ₃ ):

1.26 - 1.86; (m, 7H; 7x cyclohexyl H); 2.47 - 2.76; (m, 2H; 2x cyclohexyl H); 3.00 - 3.16; (m, 1H; cyclohexyl H); 3.93; (S .; 6H 2 O-CH _3); 4.83 - 5.15; (m .; 4H, _N-CH2, O-CH =; 6.80 to 6.97; (m .; 3H, arom. H), 7.15 to 7.47; (m .; 9H, arom H).

Example 123)

Preparation of (cis} -2- {6- / 4- (3,4-dimethoxyphenyl) -1-oxo-4a, 5,8,8a-tetrahydrofitalazin-2-yl) -hexyloxy} -benzoic acid sodium salt

Mixture prepared by mixing 4.0 g; (cis) -4- (3,4-dimethoxyphenyl) -2- (4-bromo-1-butyl) -4a, 5,8,8a-tetrahydro-2H-phthalazin-1-one; obtained under Example 114 above); further 3.0 g; ethyl salicylate; and 3.0 g; potassium carbonate; in 100.0 mL of dimethylformamide was heated at 100.0 ° C; for 2.0 hours.

After the previous operation described above, the reaction mixture was evaporated; and the resulting residue was partitioned between aqueous potassium carbonate; and ethyl acetate. After separation organic; and the organic phase was evaporated; and the residue was dissolved in the mixture obtained by mixing 100.0 ml; methanol; 100.0 mL, tetrahydrofuran; and 200.0 ml; 2N sodium hydroxide solution.

The mixture was heated at 60.0 ° C for 2.0 hours; and then evaporated. After extraction with ethyl acetate, the compound was purified by chromatography; and precipitated from ether; together with a concentrated solution of sodium ethoxide in ethanol.

After crystallization from tetrahydrofuran: diethyl ether; the desired was obtained; the title compound.

Mp: 141.0-144.0 ° C;

Example 124)

Preparation of (cis) -4- (3,4-dimethoxyphenyl) -2- (tetrahydropyran-4-yl) -4a, 5,8,8a-tetrahydro-2H-phthalazin-1-one

Analogously to Example 35 above; was from (cis) -2- (3,4-dimethoxybenzoyl) -1,2,3,6-tetrahydrobenzoic acid as the starting material; and obtained in the context of Example C) described below; and 4-hydrazintetrahydropyran, the title compound was obtained, which was crystallized from methanol.

-53 CZ 293815 B6

Mp 175.0-177.0 ° C;

Example 125)

Preparation of (cis) -4- (3,4-dimethoxyphenyl) -2- (tetrahydrothiopyran-4-yl) -4a, 5,8,8a-tetrahydro-2H-phthalazin-1-one

Analogously to Example 35 above; was from (cis) -2- (3,4-dimethoxybenzoyl) -1,2,3,6-tetrahydrobenzoic acid as the starting material; and obtained in the context of Example C) described below; and 4-hydrazintetrahydrothiopyran; the title compound was obtained, which was crystallized from methanol.

Mp: 140.0-141.0 ° C;

Example 126)

Preparation of (cis) -4- (3,4-dimethoxyphenyl) -2- (2-benzyloxybenzyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one

Analogous to the procedure described above in Example 78); was from (cis) -4- (3,4-dimethoxyphenyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one; as a starting material; and obtained as described in Example 1) above; and 2-benzyloxybenzyl chloride, the title compound, which was purified by chromatography, eluting with ethyl acetate: petroleum ether; (bp 60.0-80.0 ° C); in a ratio of 1.0: 3.0; as eluent.

Melting point: colorless; oil consistency 1 H-NMR; (CDC1 _3):

1.22 - 1.83; (m, 7H; 7x cyclohexyl H); 2.41 - 2.73; (m, 2H; 2x cyclohexyl H); 3.00 - 3.16; (m, 1H; cyclohexyl H); 3.91; (s .; 3H, _O-CH3); 3.93; (s .; 3H, _O-CH3); 4.83 - 5.16; (m .; 4H, _{N-CH2, O-CH2);} 6.80 - 6.97; (m, 3H, Ar-H); 7.15 - 7.48; (m, 9H; Ar-H).

Starting compounds

Example A)

Preparation of 2- (3,4-dimethoxybenzoyl) - [cis] -cyclohexanecarboxylic acid

To the suspension, prepared by mixing 0.50 mol of aluminum chloride in 1.0 liter of dichloromethane, was slowly added; at 0 ° C; 0.50 mol of 1,2-dimethoxybenzene.

After the preceding operation, cis-cyclohexane-1,2-dicarboxylic anhydride was added to the resulting reaction mixture; and the mixture was heated to reflux for 8.0 hours; and then poured on ice. After separation of the organic and aqueous phases, the organic layer was dried with magnesium sulfate; and evaporated.

The resulting residue was washed with diethyl ether; and dried; and the desired was obtained; the title compound.

Melting point: 171.0-175.0 ° C;

-54GB 293815 B6

Example B)

Preparation of 2- (3,4-dimethoxybenzoyl) - [trans] -cyclohexanecarboxylic acid

Analogous to that described for the preparation of the preceding compound; designated herein as Compound A); was from trans-cyclohexane-1,2-dicarboxylic acid anhydrides; and 1,2-dimethoxybenzene as starting materials; prepared title compound; designated Compound B).

Mp 202.0-205.0 ° C;

Example C)

Preparation of (cis) -2- (3,4-dimethoxybenzoyl) -1,2,3,6-tetrahydrobenzoic acid

In an analogous manner to that described in Example A) above; was from 1,2-dimethoxybenzene; and cis-1,2,3,6-tetrahydrophthalic anhydrides; as starting materials; prepared title compound; designated as Compound C).

Melting point: 110.0-112.0 ° C

Example D)

Preparation of 2- (3-cyclopentyloxy-4-methoxybenzoyl) -cis-cyclohexanecarboxylic acid

To the solution prepared by dissolving 16.30 g; (60.0 mmol); 4-bromo-2-cyclopentyloxy-1-methoxybenzene; in 200.0 mL of tetrahydrofuran; and cooled in a bath containing a mixture of ethanol and nitrogen; to minus 90.0 ° C; was added dropwise; 41.0 ml; (66.0 mmol); butyllithium; with stirring; and cooling to maintain the temperature of the reaction mixture below minus 80.0 ° C.

Then, after the last addition, the reaction mixture was stirred for a further 15.0 minutes. After the previous operation described above, the reaction mixture was quickly added; under nitrogen, to a solution obtained by dissolving 11.10 g; (72.0 mmol); cis-1,2-cyclohexanedicarboxylic acid anhydrides; in 200.0 ml; tetrahydrofuran; and pre-cooled to minus 90.0 ° C.

After the reaction mixture was stirred at minus 80.0 ° C; ammonium chloride in solid form was added over 2.0 hours; and the reaction mixture was slowly warmed to room temperature. Subsequent addition of 300.0 ml; water to the mixture, the inorganic layer was shaken with 200.0 ml; ethyl acetate. After separation of the aqueous and organic phases, the combined organic extractors were washed with 300.0 ml; water; and then 2x; 300.0 ml each; brine and which were after drying with magnesium sulfate; evaporated under reduced pressure.

The resulting residue was dissolved in dichloromethane; and purified by chromatography using a mixture prepared by mixing petroleum ether; (bp 60.0-95.0 ° C); and ethyl acetate, 7: 13.0; as eluent.

After recrystallization from a mixture of petroleum ether; (bp 60.0-95.0 ° C); and ethyl acetate; 10.10 g were obtained; the title compound; as a white solid; designated as Compound D).

Melting point: 120.0-121.0 ° C;

-55GB 293815 B6

Example E)

Preparation of (cis) -2- (3-cyclopentyloxy-4-methoxybenzoyl) -1,2,3,6-tetrahydrobenzoic acid

Solution prepared by dissolving 100.0 mmol; 1-bromo-3-cyclopentyloxy-4-methoxybenzene; in tetrahydrofuran, was slowly added to a mixture of 1.10 equivalents of magnesium.

After completion of the previous operation described above, the resulting reaction mixture was heated to reflux; for 5.0 hours; and then allowed to stand at room temperature; for 18.0 hours.

The reaction mixture was then slowly added; at 0 ° C; to a solution prepared by mixing (cis) -1,2,3,6-tetrahydrophthalic anhydride; in tetrahydrofuran. Upon completion of the above operation, the reaction mixture was heated to reflux for 6.0 hours; and then left to stand at room temperature for 18 hours. Subsequently, the mixture was mixed with ammonium chloride; and the solvent was removed under reduced pressure.

The resulting residue was acidified with concentrated hydrochloric acid; and this mixture was extracted with diethyl ether. After separation of aqueous; and the organic phase, the organic layer was dried; with magnesium sulfate; and evaporated.

The residue was dissolved in dichloromethane; and the resulting solution was filtered through silica. After subsequent evaporation of the dichloromethane solution, the compound was recrystallized from diethyl ether; to give the title compound (Compound E).

Mp: 114.0-115.0 ° C;

Example F)

Preparation of (cis) -2- (3-ethoxy-4-methoxybenzoyl) -1,2,3,6-tetrahydrobenzoic acid

In an analogous manner to that described in Example D) above; was from 1-bromo-3-ethoxy-4-methoxybenzene; and tetrahydrophthalic anhydride; as starting materials; prepared title compound; designated Compound F).

Mp 132.0-135.0 ° C;

Example G)

Preparation of 2- (3,4-diethoxybenzoyl) - [cis] -cyclohexanecarboxylic acid

In an analogous manner to that described in Example A) above; was from 1,2-diethoxybenzene; and cis-hexahydrophthalic anhydride as starting materials; ready prepared; the title compound; designated Compound G).

Melting point: low solid. @ 1 H-NMR; (CDC1 ₃ ): (nuclear magnetic resonance spectra)

-56GB 293815 B6

1.28 - 2.27; (m .; 14H, 8x-cyclohexane H; 2 C-CH _3); 2.66; (quintet; J = 4.80 Hz; 1H; cyclohexane; H); 3.91 - 3.97; (m .; 1H, C-CH (C) from 4.01 to 4.25; (m .; 4H, 2x, _O-CH2); 6.89, (d .; J = 8.20 Hz 1H, aromatic H), 7.48-7.53 (m, 2H, aromatic H).

Example H)

Preparation of (cis) -4- (4-methoxy-3-hydroxyphenyl) -2-cyclopentyl-4a, 5,8,8a-tetrahydro-2H-phthalazin-1-one

Solution prepared by dissolution 3.30 g; the compounds obtained in Example 21); ie (cis) -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-cyclopentyl-4a, 5,8,8a-tetrahydro-2H-phthalazin-1-one; and 2.0 g; p-toluenesulfonic acid; in 15.0 ml; toluene, was heated to reflux; for 4.0 hours.

After completion of the above operation, the reaction mixture was cooled to room temperature and then washed with aqueous sodium carbonate. After separation of the aqueous and organic phases, the toluene solution was dried with magnesium sulfate, and evaporated.

The resulting residue was recrystallized from diethyl ether; and petroleum ether; (bp 60.0-80.0 ° C); and the title compound was obtained; designated as Compound H).

Melting point: 142.0-144.0 ° C;

Example I)

Preparation of (c is) -4- (4-methoxy-3-hydroxyphenyl) -2-cycloheptyl-4a, 5,8,8a-tetrahydro-2H-phthalazin-1-one

Analogous to the procedure described above for the preparation of the preceding Compound H); was from the compound obtained in Example 26; described above; ie (cis) -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-cyclopentyl-4α, 5,8,8α-tetrahydro-2H-phthalazin-1-one; as a starting material; ready prepared; the title compound; designated as Compound I).

Melting point: 171.0 ° C;

Example K)

Preparation of 5-3 (-nitrophenyl) tetrazole

Mixture prepared by mixing 14.80 g; 4-nitrobenzonitrile; 32.0 g; ammonium chloride; and 39, Og; sodiumazide; (sodium azoimide); in 150.0 ml; dimethylformamide; was heated at 120.0 ° C; for 2.0 hours.

After the previous operation described above, the solvent from the reaction mixture was evaporated; and the resulting residue was partitioned between 2N hydrochloric acid solution; and ethyl acetate. After separation of the organic and aqueous phases, the organic layer was dried and evaporated. The residue was washed with ether; and dried.

The title compound was obtained; identified as Compound K).

Mp: 101.0-102.0 ° C;

-57GB 293815 B6

Example L)

Preparation of 2-benzyl-5- (4-nitrophenyl) -tetrazole

Mixture prepared by mixing 12.0 g; Compounds K); ie 5- (3-nitrophenyl) tetrazole; obtained as described in Example K) above; and 20.0 g; potassium carbonate; and 12.0 g; benzyl chloride; in 100.0 ml; dimethylformamide, was heated at 100.0 ° C; for 3.0 hours.

After the previous operation described above, the solvent was evaporated from the reaction mixture; and the resulting residue was shaken between water; and ethyl acetate. After separation of the organic and aqueous phases, the organic layer was dried with magnesium sulfate; and evaporated.

The residue was washed with diethyl ether; and dried; and the title compound was obtained; designated as Compound L).

Melting point: 139.0-141 ° C;

Example M)

Preparation of 2-benzyl-5- (4-aminophenyl) -tetrazole

Analogously to Example 74 above; was from Compound L); i.e. 2-benzyl-5- (4-nitrophenyl) tetrazole; obtained in the framework of the above-described Example L); the title compound (M) prepared; by evaporating the solvent and dissolving the resulting residue in ethyl acetate; and the obtained solution was washed with water; and, after drying with magnesium sulfate, was concentrated under reduced pressure.

The concentrated solution was filtered through silica; and evaporated; and washing the resulting residue with diethyl ether; and drying to afford the title compound; which has been referred to herein as Compound M).

Mp: 130.0-132.0 ° C;

Example N)

Preparation of 2-benzyl-5- (4-hydrazinophenyl) -tetrazole

K. a solution prepared by dissolving 6.50 g; Compounds M); ie 2-benzyl-5- (4-aminophenyl) tetrazole; obtained in the framework of the above-described Example M); in 20.0 ml; 2N hydrochloric acid solution; a solution obtained by dissolving 1.90 g was slowly added; sodium nitrite; in 10.0 mL, concentrated hydrochloric acid; and then yet; (at 0 ° C; solution of 17.0 g; stannous chloride, dihydrate; in 20.0 ml; water).

After 30.0 minutes, the resulting precipitate was filtered from the reaction mixture; and after thorough washing with brine, it was dried.

The title compound was obtained and was designated as Compound N).

Mp: 182.0-185.0 ° C;

-58GB 293815 B6

Example O)

Preparation of 2-ethyl-5- (4-hydrazinophenyl) -tetrazole

Mixture prepared by mixing 35.0 mol; 2-ethyl-5- (4-nitrophenyl) tetrazole; prepared in an analogous manner to that described above for the preparation of Compound L); and 15.0 g; irons; in a mixture of 300.0 ml; ethanol; and 80.0 ml; water; at 65.0 ° C; was reacted with 10.0 ml within 45.0 minutes; 2N hydrochloric acid solution.

After the previous operation described above, the reaction mixture was filtered; and the solvent was evaporated. The resulting residue was washed with ethyl acetate; and was used without any further purification in the next step.

To the solution obtained by dissolving the above-mentioned residue; ie 2-ethyl-5- (4-aminophenyl) tetrazole; in 20.0 ml; 2n hydrochloric acid solution; a solution was slowly added; prepared by dissolving 2.20 g; sodium nitrite; in 10.0 ml of concentrated hydrochloric acid. The reaction mixture was then added at 0 ° C; a solution obtained by dissolving 22.0 g; stannous chloride. dihydrate; in 25.0 ml; water; and the resulting reaction mixture was extracted with tetrahydrofuran after 30.0 minutes.

After subsequent separation of the organic and aqueous phases, the organic layer was washed with a single solution of aqueous sodium carbonate solution saturated with sodium chloride. The organic solution was then dried with potassium carbonate; and evaporated.

The resulting residue was used in the next step without further purification; and referred to herein as Compound O).

Commercial use

The compounds encompassed by the invention exhibit useful pharmacological properties which make them industrially useful.

As selective inhibitors of cyclic nucleotide phosphodiesterase; (especially type 4); on the one hand, they are suitable as bronchial drugs; (for the treatment of airway obstruction; due to their dilatation effect, but also due to their ability to accelerate; or to regulate respiratory stimulation); and for the elimination of erectile dysfunction, due to their vasodilating action, but also specifically for the treatment of disorders, particularly of inflammatory origin, e.g. of the respiratory tract; (prophylaxis of asthma); skin; intestines; eyes; centrally of the nervous system; (CNS); and joints that are mediated by mediators, such as histamine; platelet activating factor; (PAF); arachidonic acid derivatives; such as leukotrienes; and prostaglandins; cytokines; interleukins; chemokines; alpha; beta; and gamma-interphetone; tumor necrosis factor; (TNF); or by free oxygen radicals; and proteases.

In this context, said compounds included in the invention are excellent with low toxicity aspects; good intestinal absorption; (high bioavailability); and extensive therapeutic clarity; and the absence of significant side effects

Because of the inhibitory properties of cyclic nucleotide phosphodiesterase; (PED); the compounds of the invention may be used in human and veterinary medicine as medicaments where, for example, they can be used in the treatment and prophylaxis of the following diseases:

Acute and chronic; (particularly inflammatory and allergen-induced); respiratory disorders of various origins; (bronchitis; allergic bronchitis; bronchial asthma); dermatoses; (particularly proliferative; inflammatory; and allergic type); such as psoriasis; (psoriasa vulgaris); toxic and aller

-59GB 293815 B6 Contact eczema; soboroic eczema; lišej; (Lichen simplex); sunburn; itching in the anorgenital area; baldness; (alopecia areata); hypertrophic scars; discoid lupus erythematosus; follicular and extensive pyoderma; endogenous and exogenous acne; acne rosacera; (rosacea); and other proliferative; inflammatory; and allergic skin disorders; furthermore, disorders based on excessive release of tumor necrophilic factor (TNF); and leukotrienes; such as arthritic-type disorders; (rheumatoid arthritis; rheumatoid spondylitis; (vertebral inflammation); osteoarthritis; and other arthritic conditions); immune system disorders; (AIDS; multiple sclerosis); various types of shock; (septic shock; endotoxin shock; sepsis induced by Gram-negative bacteria; toxic shock syndrome; and ARDS; ie adult respiratory distress syndrome; as well as generalized gastrointestinal inflammation (Crohn's disease; and ulcerative colitis); allergic-based disorders; and / or immunological false reactions in the upper part of the respiratory tract; (pharynx; nose); and adjacent areas; (paranasal sinuses; eyes); such as allergic rhinitis; (allergic rhinitis); and paranasal sinusitis; (sinusitis); rhinitis and sinusitis; allergic conjunctivitis; (allergic conjunctivitis), as well as nasal polyps;

but also cardiac disorders that can be treated with cyclic phosphodiesterase inhibitors. nucleotides such as cardiac insufficiency; or disorders that can be treated as a result of tissue relaxation with PDE inhibitors; such as erectile dysfunction; or renal colic; and urethra plugs; in connection with kidney stones; as well as CNS diseases; such as depression; and dementia; due to atherosclerosis.

The invention further relates to methods of treatment of mammals; including people suffering from one of the aforementioned diseases.

The treatment procedure is characterized in that it is administered therapeutically active and pharmacologically active; and a tolerated amount of one; or more compounds included in the invention; to a sick mammal.

The invention further relates to medicaments included in the invention for the treatment and / or prophylaxis of diseases, in particular of the aforementioned diseases.

The invention also relates to the use of the compounds encompassed by the invention for the production of medicaments which are useful for the treatment and / or prophylaxis of the aforementioned diseases.

The invention further relates to medicaments for the treatment and / or prophylaxis of said diseases which comprise one or more compounds included in the invention.

Drugs are prepared by procedures known per se; and a person of ordinary skill in the art. Like drugs, the compounds included in the invention are (= active compounds); used either as such; or preferably in combination with suitable, pharmaceutical excipients; eg in the form of tablets; scored tablets; capsules; suppositories; plasters; emulsions; suspensions; gels; or solutions; wherein the content of active compound is preferably between 0.1% and 95%.

The practitioner in the relevant field is familiar with his / her expertise; with excipients which are suitable for the preparation of the desired pharmaceutical dosage forms.

In addition to solutions, gel-forming ingredients, ointment bases; and other active excipients; for example, antioxidants; dispersing agents; emulsifiers; preservatives; solubilizers; or components to facilitate the penetration of the active ingredients into the respective target areas.

For the treatment of respiratory-tract disorders, the compounds may be; included in the invention, preferably also administered by inhalation. For this purpose, said compounds are applied either directly;

-60GB 293815 B6 in powder form (preferably in micronized form); or atomized solutions; or a suspension; containing them.

From these aspects of formulation preparation, a detailed reference is made, for example, to the European patent; No. 163.965.

For the treatment of dermatoses, the compounds encompassed by the invention are especially applied in the form of medicaments suitable for topical use. For the preparation of these drugs, the compounds are included in the invention; (= active compounds); preferably mixed with suitable pharmaceutical; auxiliary components; and further processed into suitable pharmaceutical dosage forms.

Suitable pharmaceutical dosage forms; are, for example, dusting; emulsion; suspension; spreye; oils; ointments; fatty ointments; creams; pastes; gels; or solutions.

The medicaments included in the invention are prepared by methods known per se. The dose of the active compounds is used in the range customary for PDE inhibitors.

Locally applied dosage forms; (eg, ointments); intended for the treatment of dermatoses, thus containing the active compounds in concentrations; eg, in the range of 0.1% to 99.0%.

The dose for inhalation administration is usually in the range of 0.1 mg; up to 3.0 mg / day.

Usual dose for systemic therapy; (per os; or i.v.); ranges from 0.03 mg; up to 3.0 mg / kg.

Biological tests

Activation of inflammatory cells is of particular importance in monitoring PDE 4 inhibition at the cellular level. By way of example, N-formyl-methionyl-leucyl-phenylalanine-induced superoxide production in neutrophil granulocytes is exemplified. This production can be measured by chemiluminescence according to McPhail Lc, Strum SL, Leone PA and Sozzani S, The neutrophil respirators burst mechanism, Immunology, Series, 57: 47-76, 1992, ed Coffey RG, Marcel Decker, Inc., New York-Basel-Hong Kong.

Agents that inhibit chemiluminescence and cytokine secretion as well as secretion mediators promoting inflammation in inflammatory cells, particularly neutrophil and aesinophilic granulocytes, T-lymphocytes, monocytes and macrophages, also inhibit PDE 4. This phosphodiesterase isoenzyme is more particularly found in phosphodiesterase granulocytes. Inhibition of this enzyme leads to an increase in the concentration of cyclic AMP within the cells and thus inhibits cell activation. Inhibition of PDE 4 derivatives according to the invention is thus a major indicator of suppression of the inflammatory response of Giembycz MA, Could isoenzyme-selective phosphodiesterase inhibitors render bronchodilator therapy redundant in the treatment of bronchial asthma, Biochem Pharmacol 43: 20412051, 1992, Torphy Tj et al., Phosphodiesterase inhibitors : new opportunities for asthma treatment, Thorax 46: 512-523, 1991, Schudt C et al., Zardaverine: a cycklic AMP PDE 3/4 inhibitor, New Drugs for Asthma Therapy, 379-402, Birkhauser Verlag Bassel 1991, Schudt C et al., Influence of Selective Phosphodiesterase Inhibitors on Human Neutrophil Function and Levels of CAMP and Ca, Neunyn-Schmiedebergs Arch. Pharmacol 344: 682-690, 1991, Nielson CP et al., Effects of Selective Phosphodiesterase Inhibitors on Polymorphonuclear Leucocyte Burst Respirators, J Allergy Clin Immunol 86: 801-808, 1990, Schada et al., The specific type 3 and 4 phospohodiesterase inhibitor zardevarine suppression of tumor necrosis factor formation by macrophages, European Jomal of Pharmacology 230: 9-14, 1993.

-61 CZ 293815 B6

PDE 4 potency inhibition

The test was carried out according to the method of Bauer and Schwab, Naunyn-Schmiederberg's Arch. Pharmacol 311, 193-198, 1980, after microtiter plate treatment. In this test, the PDE reaction is carried out in the first step. In the second step, the resulting 5'-nucleotide is cleaved to a non-charged nucleoside by treatment with Crotalus Atrox 5'-nucleotidase. In the third step, the nucleoside is separated from the charged substrate on an ion exchange column. The column is eluted directly into small vials using 2 ml of 30 mM ammonium formate pH 6.0 with addition of 2 ml of scintillation fluid to demonstrate activity.

Inhibition values, measured as log IC ₅₀ in mol / L, were greater than 7.5 for the following substances for which the measurement was made. Compound numbers corresponding to those of the individual examples. These are compounds 10 to 33, 40, 41, 50, 52 to 55, 57, 59 to 64, 66 to 73, 75 to 82, 84, 86, 88 to 111, 115, 116, 118 to 121 and 123 to 125 .

Claims (10)

PATENT CLAIMS Phthalazinone derivatives of the general formula I in which: R1 is C1 -C4 alkoxy optionally fully or predominantly substituted by fluorine atoms, R 2 is C 1 -C 8 alkoxy, C 3 -C 7 cycloalkoxy, C 3 -C 7 cycloalkylmethoxy or C 1 -C 4 alkoxy, wholly or predominantly substituted by fluorine atoms, R3 and R4 are hydrogen or together form a chemical bond, R 5 has the meaning R 6 or represents one of the groups -C _m H _{2 m} R _H2n --C (O) R8, -CH (R9) ₂ or -C _p H ₂ p -Ar wherein R6 is hydrogen, alkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, cycloalkylmethyl of 3 to 7 carbon atoms in the alkyl moiety, alkenyl or alkynyl of 3 to 7 carbon atoms, phenylalkenyl of 3 to 4 carbon atoms in the alkenyl moiety, polycycloalkyl of 7 to 10 carbon atoms, naphthyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, quinazolinyl, quinoxalinyl, cinolinyl, isoquinolyl, quinolyl, indanyl, benzoxazolyl, benzothiazolyl, oxazolyl, thiazolyl, -62EN 293815 B6 N-methylpiperidyl, tetrahydropyranyl, tetrahydrothiapyranyl or phenyl, unsubstituted or substituted with groups R61 and / or R62, wherein: R61 represents alkyl or alkoxy of 1 to 4 carbon atoms, nitro, halogen, carboxyl, carboxalkyl, alkoxycarbonyl, hydroxyalkyl, amino, mono- or dialkylamino, alkylcarbonylamino, aminocarbonyl, mono- or dialkyl-amino-carbonyl, dialkylamino, mono- or dialkylamino; (C 1 -C 4) alkyl, 4-methylphenylsulfonamido, tetrazol-5-yl, 2-yl-tetrazol-5-yl with C 1 -C 4 alkyl or 2-benzyltetrazol-5-yl; and P62 represents an alkyl or alkoxy group having from 1 to 4 carbon atoms, a nitro group or a halogen atom, R 7 is hydroxy, halogen, cyano, nitro, nitroxy -O-NO 2, carboxyl, carboxyphenyloxy, phenoxy, C 1 -C 4 alkoxy, C 3 -C 7 cycloalkoxy, C 3 -C 7 cycloalkylmethoxy , alkylcarbonyl, alkylcarbonyloxy, alkylcarbonylamino, alkoxycarbonyl, aminocarbonyl, mono- or dialkylaminocarbonyl, amino, mono- or dialkylamino of 1 to 4 carbon atoms in the alkyl moieties or piperidyl, piperazinyl, pyrrolidinyl, or unsubstituted or unsubstituted or unsubstituted or unsubstituted or unsubstituted or unsubstituted or unsubstituted or unsubstituted; R72, R 71 represents hydroxy, alkyl, hydroxyalkyl or alkoxycarbonyl of 1 to 4 carbon atoms in each alkyl moiety, R 72 is C 1 -C 4 alkyl, carboxy, aminocarbonyl or C 1 -C 4 alkoxycarbonyl, R 8 is phenyl, naphthyl, phenanthrenyl or anthracenyl unsubstituted or substituted with R 81 and / or R 82; R 81 represents hydroxy, halogen, cyano, alkyl or alkoxy of 1 to 4 carbon atoms, carboxy, aminocarbonyl, mono- or dialkylamino carbonyl, alkylcarbonyloxy, alkoxycarbonyl, amino, mono- or dialkylamino, alkylcarbonylamino or 4-alkylcarbonylamino; carbon in the alkyl or alkoxy moiety, wherein the C 1 -C 4 alkoxy group is optionally fully or predominantly substituted by a fluorine atom and R 82 represents a hydroxy group, a halogen atom, an alkyl or alkoxy group having from 1 to 4 carbon atoms or an alkoxy group having from 1 to 4 carbon atoms, totally or predominantly substituted by fluorine atoms, R 9 represents-C _q H _2q -phenyl, Ar represents unsubstituted phenyl, naphthyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolyl, quinolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, N-benzosuccinimidyl, imidazolyl, thiazolyl, thrazolyl, thrazolyl, thrazolyl, thrazolyl, thrazolyl, thrazolyl, thrazolyl, 2-alkylthiazol-4-yl of 1 to 4 carbon atoms in the alkyl moiety or phenyl substituted with R10 and / or R11, R 1 Notified hydroxy, halogen, nitro, C 1 -C 4 alkyl, trifluoromethyl, C 1 -C 4 alkoxy, carboxy, carboxyalkyl, alkylcarbonyloxy, alkoxycarbonyl, amino, mono- or dialkylamino, alkylcarbonylamino or amino-carbocarbonyl; (C-C alkyl alkyl) alkyl moieties; -63EN 293815 B6 R1 is hydroxy, halogen, nitro, alkyl or alkoxy of 1 to 4 carbon atoms, 5 m is an integer of 1 to 8, n is an integer of 1 to 4, p is an integer of 1 to 6, q is an integer of 0 to 2, and salts of these compounds. The phthalazinone derivatives of claim 1, wherein: R1 is C1 -C4 alkoxy optionally fully or predominantly substituted by fluorine atoms, 20 R2 is C1-C8alkoxy, C3-C7cycloalkoxy, C3-C7cycloalkylmethoxy or C1-C4alkoxy, fully or predominantly substituted by fluorine atoms, R3 and R4 are hydrogen or together form a chemical bond, R 5 has the meaning R 6 or represents one of the groups -C _m H 2 _R 7, -C _n H 2 _n -C (O) R8, -CH (R9) 2 or -C _p H ₂ p -Ar wherein R6 is hydrogen, alkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, 30 cycloalkylmethyl of 3 to 7 carbon atoms in the alkyl moiety, alkenyl or alkynes 1 in each case of 3 to 7 carbon atoms; 7-carbon atoms, phenylalkenyl of 3 to 4 carbon atoms in the alkenyl moiety, bomyl, norbomyl, adamantyl or phenyl, unsubstituted or substituted with groups R61 and / or R62, wherein 35 R 61 represents an alkyl or alkoxy group having from 1 to 4 carbon atoms, a nitro group or a halogen atom, R 62 is C 1 -C 4 alkyl, nitro or halogen; 40 R 7 is hydroxy, halogen, cyano, nitro, carboxyl, phenoxy, C 1 -C 4 alkoxy, C 3 -C 7 cycloalkoxy, C 3 -C 7 cycloalkylmethoxy, alkylcarbonyl, alkylcarbonyl, alkylcarbonyl, alkylcarbonyl, alkylcarbonyl, alkylcarbonyl, alkylcarbonyl, alkylcarbonyl, alkylcarbonyl, alkylcarbonyl, alkylcarbonyl, alkylcarbonyl alkoxycarbonyl, aminocarbonyl, mono- or dialkylaminocarbonyl, amino, 1 mono- or dialkylamino in each case C 1 -C 4 alkyls or piperidyl, piperazinyl, pyrrolidinyl, or morpholinyl, unsubstituted or substituted with R 71 and / or R 72, R 71 represents hydroxy, alkyl, hydroxyalkyl or alkoxycarbonyl of 1 to 4 carbon atoms in each alkyl moiety, R 72 represents C 1 -C 4 alkyl, carboxy, aminocarbonyl or C 1 -C 4 alkoxycarbonyl, R 8 represents phenyl, naphthyl, phenathrenyl or anthracenyl unsubstituted or substituted by 55 R 81 and / or R 82 groups, -64GB 293815 B6 R 81 represents hydroxy, halogen, cyano, alkyl or alkoxy of 1 to 4 carbon atoms, carboxy, aminocarbonyl, mono- or dialkylamino carbonyl, alkylcarbonyloxy, alkoxycarbonyl, amino, mono- or dialkylamino, alkylcarbonylamino or 4-alkylcarbonylamino; carbon in the alkyl or alkoxy moiety, wherein the C 1 -C 4 alkoxy group is optionally fully or predominantly substituted by a fluorine atom and R 82 represents a hydroxy group, a halogen atom, an alkyl or alkoxy group having from 1 to 4 carbon atoms or an alkoxy group having from 1 to 4 carbon atoms, totally or predominantly substituted by fluorine atoms, R 9 is -C _q H ₂ q -phenyl, Ar represents unsubstituted phenyl, naphthyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, quinazolinyl, quinoxalinyl, cinnolinyl, isoquinolyl, quinolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, thiazolyl, thiazolyl, thiazolyl, thiazolyl, thiazolyl, thiazolyl, thiazolyl -yl of 1 to 4 carbon atoms in the alkyl moiety or phenyl substituted with R 10 and / or R 11, R 10 represents hydroxy, halogen, nitro, C 1 -C 4 alkyl, trifluoromethyl, C 1 -C 4 alkoxy, carboxy, carboxyalkyl, alkylcarbonyloxy, alkoxycarbonyl, amino, mono- or dialkylamino, alkylcarbonylamino or aminocarbonylamino or aminocarbonyl; (C-C alkyl alkyl) alkyl moieties; R1 is hydroxy, halogen, nitro, alkyl or alkoxy of 1 to 4 carbon atoms, m is an integer of 1 to 8, n is an integer of 1 to 4, p is an integer of 1 to 6, q is an integer of 0 to 2 as well as salts of these compounds. The phthalazinone derivatives of claim 1, wherein: R1 is C1 -C4 alkoxy or C1 -C2 alkoxy, wholly or predominantly substituted by fluorine, R 2 is C 1 -C 4 alkoxy, C 3 -C 7 cycloalkoxy, C 3 -C 7 cycloalkylmethoxy or C 1 -C 2 alkoxy, wholly or predominantly substituted by fluorine, R3 and R4 represent hydrogen atoms or together form another chemical bond, R 5 represents a group as defined by R 6 or one of the groups -C _m H 2 in _-R 7, -C _n H 2 _n -C (O) R 8, -CH (R 9) ₂ or -CpH ₂ p -Ar, wherein R6 is hydrogen, alkyl of 1 to 8 carbon atoms, cycloacyl of 3 to 8 carbon atoms, cycloalkylmethyl of 3 to 7 carbon atoms in the cycloacyl moiety, alkenyl or alkynyl of 3 to 8 carbon atoms each -65GB 293815 B6 7 carbon atoms, phenylalkenyl of 3 to 4 carbon atoms in the alkenyl moiety, bomyl, norbomyl, adamantyl, naphthyl, pyridyl, quinoxalinyl, indanyl, benzothiazolyl, N-methylpiperidyl, tetrahydropyranyl, tetrahydrothiapyranyl or phenyl, unsubstituted or substituted with R61 and / or R62 where R61 represents alkyl or alkoxy of 1 to 2 carbon atoms, nitro, halogen, carboxy, carboxyalkyl, alkoxycarbonyl, hydroxyalkyl, amino, mono or dialkylamino, aminocarbonyl, aminosulfonyl, mono- or dialkylaminosulfonyl, 4-methylphenylsulfonamido, tetrazolyl, tetrazol, 2-alkylthetrazol-5-yl or 2-benzyltetrazol-5-yl with alkylene moieties of 1 to 4 carbon atoms, R 62 is alkyl or alkoxy of 1 to 2 carbon atoms, nitro or halogen, R7 is hydroxyl, halogen, carboxyl, nitroxy group -O-NO _2, phenoxy, karboxyfenyloxyskupinu, alkoxy, alkylcarbonyl, alkylcarbonyloxy, alkylcarbonylamino, alkoxycarbonyl, aminocarbonyl, mono- or dialkylaminocarbonyl, amino, mono- or dialkylamino each having 1 to 4 carbon atoms in alkyl moieties, or piperidyl, piperazinyl or morpholinyl, optionally substituted with R71 and / or R72, wherein R 71 represents hydroxy, alkyl, hydroxyalkyl or alkoxycarbonyl, wherein the alkyl groups contain 1 to 4 carbon atoms and R 72 represents alkyl, carboxy, aminocarbonyl or alkoxycarbonyl wherein the alkyl groups contain 1 to 4 carbon atoms, R 8 is phenyl or naphthyl, optionally substituted with R 81 and / or R 82, wherein R81 is hydroxy, halogen, alkyl, alkoxy, alkylcarbonyloxy, alkylcarbonylamino, C1 -C4 alkyl or C1 -C2 alkoxy, fully or predominantly substituted by fluorine; and R82 represents a halogen atom, an alkyl or alkoxy group having from 1 to 4 carbon atoms, R 9 represents -C _q H _2q -phenyl, Ar is unsubstituted phenyl, naphthyl, pyridyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, N-benzosuccinimidyl, imidazolyl, oxazolyl, thiazolyl, 2-alkylthiazol-4-yl with C 1 -C 2 alkyl or phenyl substituted with R 10 and / or Rll where R1 Notified hydroxy, halogen, alkyl, trifluoromethyl, alkoxy, carboxyl, carboxyalkyl, alkylcarbonyloxy or alkoxycarbonyl, wherein the alkyl groups or moieties contain 1 to 4 carbon atoms, R11 is hydroxy, halogen, alkyl or alkoxy of 1 to 4 carbon atoms, m is an integer of 1 to 8, n is an integer of 1 to 4, p is an integer of 1 to 6, Q represents an integer from 0 to 1, as well as salts thereof. The phthalazinone derivative according to claim 1, wherein: R1 is methoxy- ethoxy- or difluoromethoxy, R2 is C1 -C4 alkoxy, difluoromethoxy, cycloalkoxy or C3 -C5 cycloalkylmethoxy, in the cycloalkyl moiety, R3 and R4 represent hydrogen atoms or together form another chemical bond, R5 represents a group selected from R6 or a group -C _{m H2m} -R7, -C _n H 2 _n -C (O) R8, -CH (R9) ₂ or -C _p H ₂ p -Ar wherein R6 is hydrogen, alkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkylmethyl of 3 to 7 carbon atoms in the cycloalkyl moiety, alkenyl or alkynyl of 3 to 4 carbon atoms, phenylalkenyl of 3 to 4 carbon atoms in the alkenyl moiety, adamantyl, pyridyl, quinoxalinyl, indanyl, benzothiazolyl, N-methylpiperidyl, tetrahydropyranyl, tetrahydrothiopyranyl or phenyl, unsubstituted or substituted by R61 and / or R62, R61 represents alkyl or alkoxy of 1 to 2 carbon atoms, nitro, halogen, carboxy, carboxyalkyl of 1 to 2 carbon atoms in the alkyl moiety, alkoxycarbonyl of 1 to 4 carbon atoms in the alkyl moiety, hydroxyalkyl of 1 to 2 carbon atoms, amino , aminosulfonyl, 4-methylphenylsulfonamido, 2-alkyltetrazol-5-yl of 1 to 2 carbon atoms in the alkyl moiety or 2-benzyltetrazol-5-yl, R 62 is alkyl of 1 to 2 carbon atoms or halogen, R 7 represents hydroxy, halogen, carboxyl, nitro, phenoxy, carboxyphenyloxy, alkoxycarbonyl, aminocarbonyl, mono- or dialkylaminocarbonyl, amino, mono- or dialkylamino or piperidyl, piperazinyl or morpholinyl, R 72 unsubstituted or / substituted by R 72 R 71 represents hydroxy, alkyl, hydroxyalkyl or alkoxycarbonyl of 1 to 4 carbon atoms in each alkyl moiety; and R 72 represents alkyl, carboxyl, aminocarbonyl or alkoxycarbonyl of 1 to 4 carbon atoms in each alkyl moiety, R 8 is phenyl or naphthyl unsubstituted or substituted with R 81; R 81 represents a halogen atom or an alkoxy group having 1 to 4 carbon atoms, R 9 represents -C _q H _2q -phenyl, Ar is unsubstituted phenyl, naphthyl, pyridyl, benzimidazolyl, benzotriazolyl, N-benzosuccinimidyl, imidazolyl, thiazolyl, 2-alkylthiazol-4-yl of 1 to 2 carbon atoms in the alkyl moiety or phenyl substituted with R10 and / or R11 R1 Notified hydroxyl, halogen, alkyl, trifluoromethyl, alkoxy, carboxyl, carboxyalkyl or alkoxycarbonyl of 1 to 4 carbon atoms in the alkyl moieties, R11 represents a halogen atom, an alkyl or alkoxy group having from 1 to 2 carbon atoms, -67EN 293815 B6 m is an integer of 1 to 8, n is an integer of 1 to 6, p is an integer of 1 or 2, q is an integer of 0 or 1, 10 as well as salts of these compounds. The compounds of formula (I) which should also be particularly emphasized are those in which the compounds of formula (I) are particularly preferred R1 is methoxy, ethoxy or difluoromethoxy, R2 is C1 -C4 alkoxy, difluoromethoxy or C3 -C5 cycloalkoxy, R3 and R4 represent hydrogen atoms or together form another chemical bond, R 5 is a group R 6 or one of -C _m H _2m -R 7, -C _n -H 2 _n -C (O) R 8, -CH (R 9) ₂ or -C _p H _2p -Ar, wherein R6 is hydrogen, alkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, cyclo25 alkylmethyl of 3 to 7 carbon atoms in the cycloalkyl moiety, alkenyl or alkynyl of 3 to 7 carbon atoms each 4 carbon atoms, phenylalkenyl of 3 to 4 carbon atoms in the alkenyl moiety or phenyl, unsubstituted or substituted by R61 and / or R62, wherein: R 61 represents an alkyl or alkoxy group having from 1 to 2 carbon atoms or a halogen atom; R 62 is alkyl of 1 to 2 carbon atoms or halogen, R7 represents hydroxy, carboxyl, phenoxy, alkoxycarbonyl, aminocarbonyl, mono- or dialkylaminocarbonyl, amino, mono- or dialkylamino or piperidinyl, piperazinyl, morpholinyl, unsubstituted or substituted by R71 and / or R72, wherein R71 represents hydroxy, alkyl, hydroxyalkyl or alkoxycarbonyl having an alkyl moiety of from 1 to 4 carbon atoms each, R 72 represents alkyl, carboxyl, aminocarbonyl, or C 1 -C 4 alkoxycarbonyl, R 8 is phenyl or naphthyl unsubstituted or substituted with R 81; R 8I is a halogen atom or a (C 1 -C 4) alkoxy group, R 9 represents -C _q H _2q -phenyl, 50 Ar represents unsubstituted phenyl, naphthyl, pyridyl, benzotriazolyl, triazolyl, 2-alkylthiazol-4-yl of 1 to 2 carbon atoms in the alkyl moiety or phenyl substituted with R 10 and / or R 11, wherein R10 represents hydroxy, halogen, alkyl, trifluoromethyl, alkoxy, carboxyl, 55 carboxyalkyl or alkoxycarbonyl each having 1 to 2 carbon atoms in the alkyl moieties, -68GB 293815 B6 R11 represents a halogen atom, an alkyl or alkoxy group having from 1 to 2 carbon atoms, m represents an integer from 1 to 6, n represents an integer from 1 or 2, p represents an integer from 1 or 2, q represents an integer from 0 or 1; of these substances. The phthalazinone derivatives according to claim 1, in which R 1 is methoxy or ethoxy, R2 is methoxy, ethoxy, difluoromethoxy, cyclopropylmethoxy or cyclopentyloxy, R3 and R4 represent hydrogen atoms or together form another chemical bond, R 5 is a group R 6 or one of -C _m H 2 _m -R 7, -C _n H 2 _n -C (O) R 8, -CH (R 9) 2 or -C p H ₂ p -Ar, R 6 is hydrogen, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 7 cycloalkylmethyl in the cycloalkyl moiety, allyl, 2-propynyl, phenyl-transprop-1-en-3-yl, adamantyl, pyridyl, quinoxalinyl, indanyl, benzothiazolyl, N-methylpiperidyl, tetrahydropyranyl, tetrahydrothiopyranyl or phenyl, unsubstituted or substituted with R61, R61 represents C1-C4alkyl, nitro, halogen, carboxyl, carboxymethyl, hydroxyalkyl of 1 to 2 carbon atoms, amino, aminosulfonyl, 4-methylphenylsulfonylamido, 2-ethyltetrazol-5-yl or 2-benzyltetrazol-5-yl , R 7 is hydroxy, halogen, carboxyl, nitroxy, phenoxy, carboxyphenyloxy, C 1 -C 4 alkoxycarbonyl, amino, methylamino, dimethylamino, dimethylaminocarbonyl, 1-piperidyl, or N-methyl 1-4 R 8 is phenyl, 2-methoxyphenyl, 4-chlorophenyl or 2-naphthyl, R 9 represents -C _q H _2q -phenyl, Ar is unsubstituted phenyl, pyridyl, benzimidazolyl, benzotriazolyl, N-benzosuccinimidyl, imidazolyl, 2-methylthiazol-4-yl or phenyl substituted with R 10 and / or R 11, R10 represents hydroxy, halogen, methoxy, trifluoromethyl, carboxyl, carboxymethyl or methoxycarbonyl, R11 is methoxy, m is an integer from 1 to 8, Η = 1, p is an integer from 1 to 6, q = 0, as well as salts of these compounds. The phthalazinone derivatives of claim 1, wherein: R 1 is methoxy, R2 is methoxy, ethoxy, difluoromethoxy, cyclopropylmethoxy or cyclopentyloxy, R3 and R4 represent hydrogen atoms or together form another chemical bond, R 5 represents a group R 6 or one of the groups -C _n H 2 _n -C (O) R 8 or -C _p H _{2 p} Ar, R6 represents alkyl of 3 to 8 carbon atoms, cycloalkyl of 5 to 8 carbon atoms, cycloalkylmethyl of 3 to 7 carbon atoms in the cycloalkyl moiety, adamantyl, quinoxalinyl, indanyl, benzothiazolyl, tetrahydropyranyl, tetrahydrothiopyranyl or phenyl, unsubstituted or substituted by R61, R 61 represents alkyl of 1 to 4 carbon atoms, nitro, halogen, carboxy, carboxymethyl, hydroxyalkyl of 1 to 2 carbon atoms, aminosulfonyl, 4-methylphenylsulfonamido, 2-ethyltetrazol-5-yl or 2-benzyltetrazol-5-yl, R 8 is phenyl or 2-naphthyl, Ar is unsubstituted phenyl, benzimidazolyl, N-benzosuccinimidyl, imidazolyl or phenyl substituted with R10, R10 is hydroxy, halogen, methoxy, trifluoromethyl or carboxyl, n = 1, p is an integer from 1 to 6, and salts thereof. Particularly preferred compounds of formula (I) in embodiment (a) are also those in which: R 1 is methoxy or ethoxy R2 is methoxy, ethoxy or cyclopentyloxy, R3 and R4 represent hydrogen atoms or together form another chemical bond, R5 is R6 or a group -C _{m H2m} -R7, -C _n H _2n -C (O) R8, -CH (R9) ₂ or Cp _H2p -Ar, wherein R 6 represents alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, cycloalkylmethyl of 3 to 7 carbon atoms in the cycloalkyl moiety, allyl, 2-propynyl, phenyl or phenyl-transprop-1-en-3-yl, -70GB 293815 B6 R7 is hydroxy, carboxyl or phenoxy, R 8 is phenyl, 2-methoxyphenyl, 4-chlorophenyl or 2-naphthyl, R 9 represents -C _q H _2q -phenyl, Ar is unsubstituted phenyl, pyridyl, benzotriazolyl, 2-methylthiazolyl-4-yl or phenyl substituted with R 10 and / or R 11, R1 Notified hydroxy, halogen, methoxy, trifluoromethyl carboxyl, carboxymethyl or methoxycarbonyl, R 11 is methoxy, m is an integer from 1 to 6, n = 1, p is an integer of 1 or 2, q = 0, and salts of these compounds. The phthalazinone derivatives according to claim 1, in which R 1 is methoxy or ethoxy, R2 is methoxy, ethoxy or cyclopentyloxy, R3 and R4 represent hydrogen atoms or together form another chemical bond, R 5 represents a group R 6 or one of the groups -C _m H _{2 m} -R 7, -C _n H 2 _n -C (O) R 8, -CH (R 9) ₂ or C _p H _{2 p} Ar, where R 6 represents alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, cycloalkylmethyl of 3 to 7 carbon atoms in the cycloalkyl moiety, allyl, 2-propynyl, phenyl or phenyl-transprop-1-en-3-yl, R7 is hydroxy, carboxyl or phenoxy, R 8 is phenyl, 2-methoxyphenyl, 4-chlorophenyl or 2-naphthyl, R 9 represents -C _q H _2q -phenyl, Ar is unsubstituted phenyl, pyridyl, benzotriazolyl, 2-methylthiazolyl-4-yl or phenyl substituted with R 10 and / or R 11, R1 Notified hydroxy, halogen, methoxy, trifluoromethyl carboxyl, carboxymethyl or methoxycarbonyl, R11 is methoxy, m is an integer from 1 to 6, -71> η = 1, p is an integer of 1 or 2, q = 0, as well as salts of these compounds. Pharmaceutical composition for the treatment of respiratory diseases, characterized in that it contains at least one phthalazinone derivative of the formula I according to claim 1 together with a pharmaceutical carrier and / or excipients. The phthalazinone derivatives of the general formula I according to claim 1 for use in therapy. Use of the phthalazinone derivatives of the general formula I according to claim 1 for the production of pharmaceutical compositions for the treatment of respiratory diseases.